@article{MTMT:34779257, title = {Generation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Astrocytes for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disease Studies}, url = {https://m2.mtmt.hu/api/publication/34779257}, author = {Dittlau, K.S. and Chandrasekaran, A. and Freude, K. and Den, Bosch L.V.}, doi = {10.21769/BioProtoc.4936}, journal-iso = {BIO-PROTOCOL}, journal = {BIO-PROTOCOL}, volume = {14}, unique-id = {34779257}, issn = {2331-8325}, year = {2024} } @article{MTMT:34779256, title = {High OXPHOS efficiency in RA-FUdr-differentiated SH-SY5Y cells: involvement of cAMP signalling and respiratory supercomplexes}, url = {https://m2.mtmt.hu/api/publication/34779256}, author = {Matrella, M.L. and Valletti, A. and Gigante, I. and De, Rasmo D. and Signorile, A. and Russo, S. and Lobasso, S. and Lobraico, D. and Dibattista, M. and Pacelli, C. and Cocco, T.}, doi = {10.1038/s41598-024-57613-x}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {34779256}, issn = {2045-2322}, year = {2024}, eissn = {2045-2322} } @article{MTMT:34308807, title = {Differentiation of human induced pluripotent stem cells into functional lung alveolar epithelial cells in 3D dynamic culture}, url = {https://m2.mtmt.hu/api/publication/34308807}, author = {Alsobaie, Sarah and Alsobaie, Tamador and Alshammary, Amal and Mantalaris, Sakis}, doi = {10.3389/fbioe.2023.1173149}, journal-iso = {FRONT BIOENG BIOTECHNOL}, journal = {FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY}, volume = {11}, unique-id = {34308807}, issn = {2296-4185}, abstract = {Introduction: Understanding lung epithelium cell development from human induced pluripotent stem cells (IPSCs) in vitro can lead to an individualized model for lung engineering, therapy, and drug testing.Method: We developed a protocol to produce lung mature type I pneumocytes using encapsulation of human IPSCs in 1.1% (w/v) alginate solution within a rotating wall bioreactor system in only 20 days without using feeder cells. The aim was to reduce exposure to animal products and laborious interventions in the future.Results: The three-dimensional (3D) bioprocess allowed cell derivation into endoderm, and subsequently into type II alveolar epithelial cells within a very short period. Cells successfully expressed surfactant proteins C and B associated with type II alveolar epithelial cells, and the key structure of lamellar bodies and microvilli was shown by transmission electron microscopy. The survival rate was the highest under dynamic conditions, which reveal the possibility of adapting this integration for large-scale cell production of alveolar epithelial cells from human IPSCs.Discussion: We were able to develop a strategy for the culture and differentiation of human IPSCs into alveolar type II cells using an in vitro system that mimics the in vivo environment. Hydrogel beads would offer a suitable matrix for 3D cultures and that the high-aspect-ratio vessel bioreactor can be used to increase the differentiation of human IPSCs relative to the results obtained with traditional monolayer cultures.}, keywords = {bioprocess; lung development; iPSCs; 3D culture; Dynamic condition}, year = {2023}, eissn = {2296-4185}, orcid-numbers = {Alsobaie, Sarah/0000-0002-1707-6461} } @article{MTMT:34308806, title = {Spinal Cord Organoids to Study Motor Neuron Development and Disease}, url = {https://m2.mtmt.hu/api/publication/34308806}, author = {Buchner, Felix and Dokuzluoglu, Zeynep and Grass, Tobias and Rodriguez-Muela, Natalia}, doi = {10.3390/life13061254}, journal-iso = {LIFE-BASEL}, journal = {LIFE-BASEL}, volume = {13}, unique-id = {34308806}, abstract = {Motor neuron diseases (MNDs) are a heterogeneous group of disorders that affect the cranial and/or spinal motor neurons (spMNs), spinal sensory neurons and the muscular system. Although they have been investigated for decades, we still lack a comprehensive understanding of the underlying molecular mechanisms; and therefore, efficacious therapies are scarce. Model organisms and relatively simple two-dimensional cell culture systems have been instrumental in our current knowledge of neuromuscular disease pathology; however, in the recent years, human 3D in vitro models have transformed the disease-modeling landscape. While cerebral organoids have been pursued the most, interest in spinal cord organoids (SCOs) is now also increasing. Pluripotent stem cell (PSC)-based protocols to generate SpC-like structures, sometimes including the adjacent mesoderm and derived skeletal muscle, are constantly being refined and applied to study early human neuromuscular development and disease. In this review, we outline the evolution of human PSC-derived models for generating spMN and recapitulating SpC development. We also discuss how these models have been applied to exploring the basis of human neurodevelopmental and neurodegenerative diseases. Finally, we provide an overview of the main challenges to overcome in order to generate more physiologically relevant human SpC models and propose some exciting new perspectives.}, keywords = {Organoids; Development; Induced pluripotent stem cells (iPSCs); in vitro disease modeling; motor neuron (MN); spinal cord (SpC); motor neuron diseases (MNDs); spinal cord organoids (SCOs)}, year = {2023}, eissn = {2075-1729}, orcid-numbers = {Rodriguez-Muela, Natalia/0000-0003-1065-1870} } @article{MTMT:33688508, title = {Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons}, url = {https://m2.mtmt.hu/api/publication/33688508}, author = {Castillo, Bautista C.M. and Sterneckert, J.}, doi = {10.3389/fcell.2022.1089970}, journal-iso = {FRONT CELL DEV BIOL}, journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, volume = {10}, unique-id = {33688508}, issn = {2296-634X}, year = {2023}, eissn = {2296-634X} } @article{MTMT:34614913, title = {The SVZ stem cell niche-components, functions, and in vitro modelling}, url = {https://m2.mtmt.hu/api/publication/34614913}, author = {Esiyok, Nesil and Heide, Michael}, doi = {10.3389/fcell.2023.1332901}, journal-iso = {FRONT CELL DEV BIOL}, journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, volume = {11}, unique-id = {34614913}, issn = {2296-634X}, abstract = {Neocortical development depends on the intrinsic ability of neural stem and progenitor cells to proliferate and differentiate to generate the different kinds of neurons in the adult brain. These progenitor cells can be distinguished into apical progenitors, which occupy a stem cell niche in the ventricular zone and basal progenitors, which occupy a stem cell niche in the subventricular zone (SVZ). During development, the stem cell niche provided in the subventricular zone enables the increased proliferation and self-renewal of basal progenitors, which likely underlie the expansion of the human neocortex. However, the components forming the SVZ stem cell niche in the developing neocortex have not yet been fully understood. In this review, we will discuss potential components of the SVZ stem cell niche, i.e., extracellular matrix composition and brain vasculature, and their possible key role in establishing and maintaining this niche during fetal neocortical development. We will also emphasize the potential role of basal progenitor morphology in maintaining their proliferative capacity within the stem cell niche of the SVZ. Finally, we will focus on the use of brain organoids to i) understand the unique features of basal progenitors, notably basal radial glia; ii) study components of the SVZ stem cell niche; and iii) provide future directions on how to improve brain organoids, notably the organoid SVZ, and make them more reliable models of human neocortical development and evolution studies.}, keywords = {VASCULATURE; subventricular zone; Stem Cell Niche; ECM; basal progenitors; Neocortex development}, year = {2023}, eissn = {2296-634X}, orcid-numbers = {Heide, Michael/0000-0002-0752-8460} } @article{MTMT:34779260, title = {Whole Cell Patch Clamp Electrophysiology in Human Neuronal Cells}, url = {https://m2.mtmt.hu/api/publication/34779260}, author = {Gabriel, R. III and Boreland, A.J. and Pang, Z.P.}, doi = {10.1007/978-1-0716-3287-1_21}, journal-iso = {METHODS MOL BIOL}, journal = {METHODS IN MOLECULAR BIOLOGY}, volume = {2683}, unique-id = {34779260}, issn = {1064-3745}, year = {2023}, eissn = {1940-6029}, pages = {259-273} } @article{MTMT:34233644, title = {Wireless Electrical Signals Induce Functional Neuronal Differentiation of BMSCs on 3D Graphene Framework Driven by Magnetic Field}, url = {https://m2.mtmt.hu/api/publication/34233644}, author = {Gao, Haoyang and Sun, Chunhui and Shang, Shuo and Sun, Baojun and Sun, Mingyuan and Hu, Shuang and Yang, Hongru and Hu, Ying and Feng, Zhichao and Zhou, Weijia and Liu, Chao and Wang, Jingang and Liu, Hong}, doi = {10.1021/acsnano.3c05725}, journal-iso = {ACS NANO}, journal = {ACS NANO}, volume = {17}, unique-id = {34233644}, issn = {1936-0851}, abstract = {Bone marrow mesenchymal stem cells (BMSCs) are suggestedas candidatesfor neurodegeneration therapy by autologous stem cells to overcomethe lack of neural stem cells in adults. However, the differentiationof BMSCs into functional neurons is a major challenge for neurotherapy.Herein, a methodology has been proposed to induce functional neuronaldifferentiation of BMSCs on a conductive three-dimensional grapheneframework (GFs) combined with a rotating magnetic field. A wirelesselectrical signal of about 10 & mu;A can be generated on the surfaceof GFs by cutting the magnetic field lines based on the well-knownelectromagnetic induction effect, which has been proven to be suitablefor inducing neuronal differentiation of BMSCs. The enhanced expressionsof the specific genes/proteins and apparent Ca2+ intracellularflow indicate that BMSCs cultured on GFs with 15 min/day rotatingmagnetic field stimulation for 15 days can differentiate functionalneurons without any neural inducing factor. The animal experimentsconfirm the neural differentiation of BMSCs on GFs after transplantation in vivo, accompanied by stimulation of an external rotatingmagnetic field. This study overcomes the lack of autologous neuralstem cells for adult neurodegeneration patients and provides a facileand safe strategy to induce the neural differentiation of BMSCs, whichhas potential for clinical applications of neural tissue engineering.}, keywords = {Electromagnetic induction; NEURONAL DIFFERENTIATION; Bone marrow mesenchymal stem cells; graphene framework; wireless electricalstimulation}, year = {2023}, eissn = {1936-086X}, pages = {16204-16220}, orcid-numbers = {Zhou, Weijia/0000-0003-4339-0435} } @article{MTMT:33918205, title = {Susceptibility of Ovine Bone Marrow-Derived Mesenchymal Stem Cell Spheroids to Scrapie Prion Infection}, url = {https://m2.mtmt.hu/api/publication/33918205}, author = {Hernaiz, Adelaida and Cobeta, Paula and Marin, Belen and Vazquez, Francisco Jose and Badiola, Juan Jose and Zaragoza, Pilar and Bolea, Rosa and Martin-Burriel, Inmaculada}, doi = {10.3390/ani13061043}, journal-iso = {ANIMALS-BASEL}, journal = {ANIMALS}, volume = {13}, unique-id = {33918205}, abstract = {Simple Summary Prion diseases are fatal and incurable neurodegenerative disorders affecting both humans and animals. The development of in vitro cellular models from naturally susceptible species such as ruminants can be very useful for the study of prion disease mechanisms and the discovery of potential therapies. Our study shows for the first time how the culture, in the form of three-dimensional spheroids of ovine mesenchymal stem cells derived from bone marrow in growth and neurogenic conditions, makes these cells more permissive to prion infection, mimicking the prion toxicity occurring in these diseases. This three-dimensional system appears as a potential in vitro model for studying prion diseases in a microenvironment approaching in vivo conditions. In neurodegenerative diseases, including prion diseases, cellular in vitro models appear as fundamental tools for the study of pathogenic mechanisms and potential therapeutic compounds. Two-dimensional (2D) monolayer cell culture systems are the most used cell-based assays, but these platforms are not able to reproduce the microenvironment of in vivo cells. This limitation can be surpassed using three-dimensional (3D) culture systems such as spheroids that more effectively mimic in vivo cell interactions. Herein, we evaluated the effect of scrapie prion infection in monolayer-cultured ovine bone marrow-derived mesenchymal stem cells (oBM-MSCs) and oBM-MSC-derived spheroids in growth and neurogenic conditions, analyzing their cell viability and their ability to maintain prion infection. An MTT assay was performed in oBM-MSCs and spheroids subjected to three conditions: inoculated with brain homogenate from scrapie-infected sheep, inoculated with brain homogenate from healthy sheep, and non-inoculated controls. The 3D conditions improved the cell viability in most cases, although in scrapie-infected spheroids in growth conditions, a decrease in cell viability was observed. The levels of pathological prion protein (PrPSc) in scrapie-infected oBM-MSCs and spheroids were measured by ELISA. In neurogenic conditions, monolayer cells and spheroids maintained the levels of PrPSc over time. In growth conditions, however, oBM-MSCs showed decreasing levels of PrPSc throughout time, whereas spheroids were able to maintain stable PrPSc levels. The presence of PrPSc in spheroids was also confirmed by immunocytochemistry. Altogether, these results show that a 3D culture microenvironment improves the permissiveness of oBM-MSCs to scrapie infection in growth conditions and maintains the infection ability in neurogenic conditions, making this model of potential use for prion studies.}, keywords = {SPHEROIDS; SCRAPIE; Mesenchymal Stem Cells; prion; 3D culture}, year = {2023}, eissn = {2076-2615} } @article{MTMT:34625559, title = {Comparative assessment of Ca2+ oscillations in 2- and 3-dimensional hiPSC derived and isolated cortical neuronal networks}, url = {https://m2.mtmt.hu/api/publication/34625559}, author = {Imredy, John P. and Roussignol, Gautier and Clouse, Holly and Salvagiotto, Giorgia and Mazelin-Winum, Ludmilla}, doi = {10.1016/j.vascn.2023.107281}, journal-iso = {J PHARMACOL TOXICOL METH}, journal = {JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS}, volume = {123}, unique-id = {34625559}, issn = {1056-8719}, keywords = {Neurotoxicity; NEURONS; calcium; SEIZURES; MOUSE; NETWORKS; In Vitro; Methods; CORTICAL NEURON; SAFETY PHARMACOLOGY; hiPSC}, year = {2023}, eissn = {1873-488X} } @article{MTMT:34308805, title = {Therapeutic effect of a hydrogel-based neural stem cell delivery sheet for mild traumatic brain injury}, url = {https://m2.mtmt.hu/api/publication/34308805}, author = {Kim, Jong-Tae and Cho, Sung Min and Youn, Dong Hyuk and Hong, Eun Pyo and Park, Chan Hum and Lee, Younghyurk and Jung, Harry and Jeon, Jin Pyeong}, doi = {10.1016/j.actbio.2023.06.027}, journal-iso = {ACTA BIOMATER}, journal = {ACTA BIOMATERIALIA}, volume = {167}, unique-id = {34308805}, issn = {1742-7061}, abstract = {Objective: There are no effective clinically applicable treatments for neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated the therapeutic effect of a new delivery method of mouse neural stem cell (mNSC) spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after mild TBI. Methods: mNSCs were isolated from the subventricular zone and subgranular zone by a hydrogel-based culture system. GFP-transduced mNSCs were generated into spheroids and wrapped into a sheet for transplantation. Male C57BL/6J mice were randomly divided into four groups: sham operation, TBI, TBI with mNSC spheroids, and TBI with mNSC spheroid sheet transplantation covering the damaged cortex. Histopathological and immunohistochemical features and cognitive function were evaluated 7, 14, and 28 days after transplantation following TBI. Results: Hydrogel-based culture systems and mNSC isolation were successfully established from the adult mice. Essential transcription factors for NSCs, such as SOX2, PAX6, Olig2, nestin, and doublecortin (DCX), were highly expressed in the mNSCs. A transplanted hydrogel-based mNSC spheroid sheet showed good engraftment and survival ability, differentiated into TUJ1-positive neurons, promoted angiogenesis, and reduced neuronal degeneration. Also, TBI mice treated with mNSC spheroid sheet transplantation exhibited a significantly increased preference for a new object, suggesting improved cognitive function compared to the mNSC spheroids or no treatment groups. Conclusion: Transplantation with a hydrogel-based mNSC spheroid sheet showed engraftment, migration, and stability of delivered cells in a hostile microenvironment after TBI, resulting in improved cognitive function via reconstruction of the damaged cortex.Statement of Significance : This study presents the therapeutic effect of a new delivery method of mouse neural stem cells spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after traumatic brain injury. Collagen/fibrin hydrogel allowed long-term survival and migratory ability of NSCs spheroids. Furthermore, transplanted hydrogel-based mNSCs spheroids sheet showed good engraftment, migration, and stability of delivered cells in a hostile microenvironment, resulting in reconstruction of the damaged cortex and improved cognitive function after TBI. Therefore, we suggest that a hydrogel-based mNSCs spheroids sheet could help to improve cognitive impairment after TBI.& COPY; 2023 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc.This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )}, keywords = {cognition; traumatic brain injury; neuroblast; Neural Stem Cells; Hydrogel support}, year = {2023}, eissn = {1878-7568}, pages = {335-347}, orcid-numbers = {Hong, Eun Pyo/0000-0001-7789-686X} } @article{MTMT:33703588, title = {Advances in Nerve Injury Models on a Chip}, url = {https://m2.mtmt.hu/api/publication/33703588}, author = {Lee, D. and Yang, K. and Xie, J.}, doi = {10.1002/adbi.202200227}, journal-iso = {ADV BIOL}, journal = {ADVANCED BIOLOGY}, volume = {7}, unique-id = {33703588}, year = {2023}, eissn = {2701-0198} } @{MTMT:34327573, title = {Clinical and Molecular Overview of Cortical Malformations}, url = {https://m2.mtmt.hu/api/publication/34327573}, author = {Pravata, M.V. and Gressens, P. and Cappello, S.}, booktitle = {Neocortical Neurogenesis in Development and Evolution}, doi = {10.1002/9781119860914.ch27}, unique-id = {34327573}, year = {2023}, pages = {595-624} } @article{MTMT:33703587, title = {Feeder cells treated with ethanol can be used to maintain self-renewal and pluripotency of human pluripotent stem cells}, url = {https://m2.mtmt.hu/api/publication/33703587}, author = {Ren, Y. and Zhang, S. and Liang, Y. and Gong, Z. and Cui, Y. and Song, W.}, doi = {10.1002/2211-5463.13538}, journal-iso = {FEBS OPEN BIO}, journal = {FEBS OPEN BIO}, volume = {13}, unique-id = {33703587}, issn = {2211-5463}, year = {2023}, eissn = {2211-5463}, pages = {279-292} } @{MTMT:34327579, title = {In vitro evaluation of biomaterials for neural tissue engineering}, url = {https://m2.mtmt.hu/api/publication/34327579}, author = {Sahin, A. and Ciki, B. and Karademir-Yilmaz, B.}, booktitle = {Biomaterials for Neural Tissue Engineering}, doi = {10.1016/B978-0-323-90554-1.00003-3}, unique-id = {34327579}, year = {2023}, pages = {367-415} } @article{MTMT:34578064, title = {Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease}, url = {https://m2.mtmt.hu/api/publication/34578064}, author = {Salcedo, Claudia and Pozo Garcia, Victoria and Garcia-Adan, Bernat and Ameen, Aishat O. and Gegelashvili, Georgi and Waagepetersen, Helle S. and Freude, Kristine K. and Aldana, Blanca I.}, doi = {10.1111/jnc.16014}, journal-iso = {J NEUROCHEM}, journal = {JOURNAL OF NEUROCHEMISTRY}, unique-id = {34578064}, issn = {0022-3042}, abstract = {Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using [C-13]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.}, keywords = {excitotoxicity; energy metabolism; APP; PSEN-1; hiPSC neurons; hiPSC astrocytes}, year = {2023}, eissn = {1471-4159} } @article{MTMT:33918202, title = {The Effect of Rosmarinic Acid on Neural Differentiation of Wartons Jelly-derived Mesenchymal Stem Cells in Two-dimensional and Three-dimensional Cultures using Chitosan-based Hydrogel}, url = {https://m2.mtmt.hu/api/publication/33918202}, author = {Salmanvandi, Mohsen and Haramshahi, Seyed Mohammad Amin and Mansouri, Elahe and Alizadeh, Akram}, doi = {10.32598/bcn.2021.2596.1}, journal-iso = {BASIC CLIN NEUROSCI}, journal = {BASIC AND CLINICAL NEUROSCIENCE}, volume = {14}, unique-id = {33918202}, issn = {2008-126X}, abstract = {Introduction: Numerous studies have shown the positive effects of rosmarinic acid on the nervous system.Rosmarinic acid as a herbal compound with anti-inflammatory effects can prevent thedestructive effect of inflammation on the nervous system. Furthermore, various studies haveemphasized the advantages of three-dimensional (3D) culture over the two-dimensional (2D) culture of cells. Methods: In this study, thermosensitive chitosan (CH)-based hydrogel as a 3D scaffoldwith the combination of chitosan, beta-glycerol phosphate and hydroxyl ethyl cellulose (CH-GP-HEC) loaded with rosmarinic acid was used to induce neuronal differentiation in humanWharton jelly stem cells. Also, cells were divided into eight groups to evaluate the effect of 3Dcell culture and to compare gene expression in different induction conditions. Results: The results ofgene expression analysis showed the highest expression of neuronal markers in Whartons jelly derived mesenchymal stem cells (WJMSCs) cultured in chitosan, beta-glycerol phosphate and hydroxyl ethyl cellulose (ch-gp-hec) loaded with differentiation medium androsmarinic acid. According to the results of gene expression, rosmarinic acid alone has a positiveeffect on the induction of expression of neural markers. This positive effect is enhanced by cellculture in 3D conditions. Conclusion: This study shows that rosmarinic acid can be considered an inexpensiveand available compound for use in neural tissue engineering. The results of this study indicatethat rosmarinic acid can be considered a cheap and available compound for use in neural tissueengineering.}, keywords = {Rosmarinic acid Neural; differentiation Hydrogel; Chitosan (CH) Wharton?s; jelly-derived mesenchymal; stem cells (WJMSCs)}, year = {2023}, pages = {117-128} } @article{MTMT:33918204, title = {Revolutionizing Disease Modeling: The Emergence of Organoids in Cellular Systems}, url = {https://m2.mtmt.hu/api/publication/33918204}, author = {Silva-Pedrosa, Rita and Salgado, Antonio Jose and Ferreira, Pedro Eduardo}, doi = {10.3390/cells12060930}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {12}, unique-id = {33918204}, abstract = {Cellular models have created opportunities to explore the characteristics of human diseases through well-established protocols, while avoiding the ethical restrictions associated with post-mortem studies and the costs associated with researching animal models. The capability of cell reprogramming, such as induced pluripotent stem cells (iPSCs) technology, solved the complications associated with human embryonic stem cells (hESC) usage. Moreover, iPSCs made significant contributions for human medicine, such as in diagnosis, therapeutic and regenerative medicine. The two-dimensional (2D) models allowed for monolayer cellular culture in vitro; however, they were surpassed by the three-dimensional (3D) cell culture system. The 3D cell culture provides higher cell-cell contact and a multi-layered cell culture, which more closely respects cellular morphology and polarity. It is more tightly able to resemble conditions in vivo and a closer approach to the architecture of human tissues, such as human organoids. Organoids are 3D cellular structures that mimic the architecture and function of native tissues. They are generated in vitro from stem cells or differentiated cells, such as epithelial or neural cells, and are used to study organ development, disease modeling, and drug discovery. Organoids have become a powerful tool for understanding the cellular and molecular mechanisms underlying human physiology, providing new insights into the pathogenesis of cancer, metabolic diseases, and brain disorders. Although organoid technology is up-and-coming, it also has some limitations that require improvements.}, keywords = {Organoids; cell culture; Disease modeling; iPSCs; organoids applications; organoids limitations}, year = {2023}, eissn = {2073-4409} } @article{MTMT:34444712, title = {Characterization of neural stem cells derived from human stem cells from the apical papilla undergoing three-dimensional neurosphere induction}, url = {https://m2.mtmt.hu/api/publication/34444712}, author = {Songsaad, A.T. and Thairat, S. and Seemaung, P. and Thongsuk, A. and Balit, T. and Ruangsawasdi, N. and Phruksaniyom, C. and Gonmanee, T. and White, K.L. and Thonabulsombat, C.}, doi = {10.1590/1678-7757-2023-0209}, journal-iso = {J APPL ORAL SCI}, journal = {JOURNAL OF APPLIED ORAL SCIENCE}, volume = {31}, unique-id = {34444712}, issn = {1678-7757}, year = {2023}, eissn = {1678-7765} } @article{MTMT:33238581, title = {Combination of EPC-EXs and NPC-EXs with miR-126 and miR-210 overexpression produces better therapeutic effects on ischemic stroke by protecting neurons through the Nox2/ROS and BDNF/TrkB pathways}, url = {https://m2.mtmt.hu/api/publication/33238581}, author = {Xu, Xiaobing and Zhang, Huiting and Li, Jiahui and Chen, Yanyu and Zhong, Wangtao and Chen, Yanfang and Ma, Xiaotang}, doi = {10.1016/j.expneurol.2022.114235}, journal-iso = {EXP NEUROL}, journal = {EXPERIMENTAL NEUROLOGY}, volume = {359}, unique-id = {33238581}, issn = {0014-4886}, abstract = {Backgrounds/aims: Neural progenitor cells (NPCs) and endothelial progenitor cell (EPCs) exhibit synergistical effects on protecting endothelial cell functions. MiR-126 and miR-210 can protect cell activities by regulating brain-derived neurotrophic factor (BDNF) and reactive oxygen species (ROS) production. Exosomes (EXs) mediate the beneficial effects of stem cells via delivering microRNAs (miRs). Here, we investigated the combi-nation effects of EXs from EPCs (EPC-EXs) and NPCs (NPC-EXs), and determined whether these EXs with miR-126 (EPC-EXsmiR-126) and miR-210 overexpression (NPC-EXsmiR-210) had better effects on hypoxia/reoxygenation (H/ R)-injured neurons and ischemic stroke (IS).Methods: Cultured neurons were subjected to hypoxia for 6 h and then co-cultured with culture medium, NPC-EXs, EPC-EXs, NPC-EXs + EPC-EXs or NPC-EXsmiR-210 + EPC-EXsmiR-126 under normoxia for 24 h. Cell apoptosis, ROS production, neurite outgrowth and BDNF level were analyzed. Permanent middle cerebral artery occlusion (MCAO) was performed on C57BL/6 mice to build IS model. The mice were injected with PBS or various EXs via tail vein 2 h after MCAO operation. After 24 h, infarct volume and neurological deficits score (NDS), neuronal apoptosis, ROS production and spine density of dendrites, and brain BDNF level were analyzed. For mechanism study, NADPH oxidase 2(Nox2) and BDNF receptor tyrosine kinase receptor B (TrkB) were determined, and TrkB inhibitor k-252a was used in in vitro and in vivo study.Results: 1) The level of miR-210 or miR-126 was increased after NPC-EXs or EPC-EXs treatment respectively. 2) In H/R-injured neurons, NPC-EXs or EPC-EXs decreased cell apoptosis and ROS production and promoted neurite outgrowth, which were associated with the downregulation of Nox2 and the increase of BDNF and p-TrkB/TrkB level. 3) In MCAO mice, NPC-EXs or EPC-EXs decreased infarct volume and NDS, reduced neural apoptosis and ROS production, and promoted the spine density of dendrites. The levels of Nox2, BDNF and p-TrkB/TrkB in mouse brain tissues changed in similar patterns as seen in the in vitro study. 4) In both cell and mouse models, combination of NPC-EXs and EPC-EXs was more effective than NPC-EXs or EPC-EXs alone on all of these effects. 5) EPC-EXsmiR-126 + NPC-EXsmiR-210 had better effects compared to NPC-EXs + EPC-EXs, which were inhibited by k-252a.Conclusion: EPC-EXsmiR-126 combined NPC-EXsmiR-210 further orchestrate the combinative protective effects of EPC-EXs and NPC-EXs on IS, possibly by protecting H/R-injured neurons through the Nox2/ ROS and BDNF/TrkB pathways.}, keywords = {NEURONS; ischemic stroke; HYPOXIA; reoxygenation; miR-126; miR-210; EPC-EXs; NPC-EXs}, year = {2023}, eissn = {1090-2430} } @article{MTMT:34305217, title = {A live-cell image-based machine learning strategy for reducing variability in PSC differentiation systems}, url = {https://m2.mtmt.hu/api/publication/34305217}, author = {Yang, Xiaochun and Chen, Daichao and Sun, Qiushi and Wang, Yao and Xia, Yu and Yang, Jinyu and Lin, Chang and Dang, Xin and Cen, Zimu and Liang, Dongdong and Wei, Rong and Xu, Ze and Xi, Guangyin and Xue, Gang and Ye, Can and Wang, Li-Peng and Zou, Peng and Wang, Shi-Qiang and Rivera-Fuentes, Pablo and Puentener, Salome and Chen, Zhixing and Liu, Yi and Zhang, Jue and Zhao, Yang}, doi = {10.1038/s41421-023-00543-1}, journal-iso = {CELL DISCOV}, journal = {CELL DISCOVERY}, volume = {9}, unique-id = {34305217}, abstract = {The differentiation of pluripotent stem cells (PSCs) into diverse functional cell types provides a promising solution to support drug discovery, disease modeling, and regenerative medicine. However, functional cell differentiation is currently limited by the substantial line-to-line and batch-to-batch variabilities, which severely impede the progress of scientific research and the manufacturing of cell products. For instance, PSC-to-cardiomyocyte (CM) differentiation is vulnerable to inappropriate doses of CHIR99021 (CHIR) that are applied in the initial stage of mesoderm differentiation. Here, by harnessing live-cell bright-field imaging and machine learning (ML), we realize real-time cell recognition in the entire differentiation process, e.g., CMs, cardiac progenitor cells (CPCs), PSC clones, and even misdifferentiated cells. This enables non-invasive prediction of differentiation efficiency, purification of ML-recognized CMs and CPCs for reducing cell contamination, early assessment of the CHIR dose for correcting the misdifferentiation trajectory, and evaluation of initial PSC colonies for controlling the start point of differentiation, all of which provide a more invulnerable differentiation method with resistance to variability. Moreover, with the established ML models as a readout for the chemical screen, we identify a CDK8 inhibitor that can further improve the cell resistance to the overdose of CHIR. Together, this study indicates that artificial intelligence is able to guide and iteratively optimize PSC differentiation to achieve consistently high efficiency across cell lines and batches, providing a better understanding and rational modulation of the differentiation process for functional cell manufacturing in biomedical applications.}, year = {2023}, eissn = {2056-5968}, orcid-numbers = {Chen, Daichao/0009-0002-7040-8266; Rivera-Fuentes, Pablo/0000-0001-8558-2828; Zhao, Yang/0000-0002-0856-2724} } @article{MTMT:34327575, title = {Porous gelatin microspheres implanted with adipose mesenchymal stromal cells promote angiogenesis via protein kinase B/endothelial nitric oxide synthase signaling pathway in bladder reconstruction}, url = {https://m2.mtmt.hu/api/publication/34327575}, author = {Zhao, J. and Yang, T. and Zhou, L. and Liu, J. and Mao, L. and Jia, R. and Zhao, F.}, doi = {10.1016/j.jcyt.2023.08.005}, journal-iso = {CYTOTHERAPY}, journal = {CYTOTHERAPY}, volume = {25}, unique-id = {34327575}, issn = {1465-3249}, year = {2023}, eissn = {1477-2566}, pages = {1317-1330} } @article{MTMT:33918203, title = {Conducting polymer-based nanostructured materials for brain-machine interfaces}, url = {https://m2.mtmt.hu/api/publication/33918203}, author = {Ziai, Yasamin and Zargarian, Seyed Shahrooz and Rinoldi, Chiara and Nakielski, Pawel and Sola, Antonella and Lanzi, Massimiliano and Truong, Yen Bach and Pierini, Filippo}, doi = {10.1002/wnan.1895}, journal-iso = {WIRES NANOMED NANOBI}, journal = {WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY}, volume = {15}, unique-id = {33918203}, issn = {1939-5116}, abstract = {As scientists discovered that raw neurological signals could translate into bioelectric information, brain-machine interfaces (BMI) for experimental and clinical studies have experienced massive growth. Developing suitable materials for bioelectronic devices to be used for real-time recording and data digitalizing has three important necessitates which should be covered. Biocompatibility, electrical conductivity, and having mechanical properties similar to soft brain tissue to decrease mechanical mismatch should be adopted for all materials. In this review, inorganic nanoparticles and intrinsically conducting polymers are discussed to impart electrical conductivity to systems, where soft materials such as hydrogels can offer reliable mechanical properties and a biocompatible substrate. Interpenetrating hydrogel networks offer more mechanical stability and provide a path for incorporating polymers with desired properties into one strong network. Promising fabrication methods, like electrospinning and additive manufacturing, allow scientists to customize designs for each application and reach the maximum potential for the system. In the near future, it is desired to fabricate biohybrid conducting polymer-based interfaces loaded with cells, giving the opportunity for simultaneous stimulation and regeneration. Developing multi-modal BMIs, Using artificial intelligence and machine learning to design advanced materials are among the future goals for this field.This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease}, keywords = {Electrospinning; 3D printing; neural recording; brain-machine interface; conductive hydrogels}, year = {2023}, eissn = {1939-0041}, orcid-numbers = {Sola, Antonella/0000-0002-8649-9388; Pierini, Filippo/0000-0002-6526-4141} } @article{MTMT:33137051, title = {Automated high-speed 3D imaging of organoid cultures with multi-scale phenotypic quantification}, url = {https://m2.mtmt.hu/api/publication/33137051}, author = {Beghin, A. and Grenci, G. and Sahni, G. and Guo, S. and Rajendiran, H. and Delaire, T. and Mohamad, Raffi S.B. and Blanc, D. and de, Mets R. and Ong, H.T. and Galindo, X. and Monet, A. and Acharya, V. and Racine, V. and Levet, F. and Galland, R. and Sibarita, J.-B. and Viasnoff, V.}, doi = {10.1038/s41592-022-01508-0}, journal-iso = {NAT METHODS}, journal = {NATURE METHODS}, volume = {19}, unique-id = {33137051}, issn = {1548-7091}, year = {2022}, eissn = {1548-7105}, pages = {881-892} } @article{MTMT:34776122, title = {Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells}, url = {https://m2.mtmt.hu/api/publication/34776122}, author = {Bierman-Duquette, R.D. and Safarians, G. and Huang, J. and Rajput, B. and Chen, J.Y. and Wang, Z.Z. and Seidlits, S.K.}, doi = {10.1002/adhm.202101577}, journal-iso = {ADV HEALTHC MATER}, journal = {ADVANCED HEALTHCARE MATERIALS}, volume = {11}, unique-id = {34776122}, issn = {2192-2640}, year = {2022}, eissn = {2192-2659} } @article{MTMT:33703589, title = {Development of an extrusion-based 3D-printing strategy for clustering of human neural progenitor cells}, url = {https://m2.mtmt.hu/api/publication/33703589}, author = {Bilkic, I. and Sotelo, D. and Anujarerat, S. and Ortiz, N.R. and Alonzo, M. and El, Khoury R. and Loyola, C.C. and Joddar, B.}, doi = {10.1016/j.heliyon.2022.e12250}, journal-iso = {HELIYON}, journal = {HELIYON}, volume = {8}, unique-id = {33703589}, year = {2022}, eissn = {2405-8440} } @article{MTMT:33289472, title = {A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids.}, url = {https://m2.mtmt.hu/api/publication/33289472}, author = {Boutin, M.E. and Strong, C.E. and Van, Hese B. and Hu, X. and Itkin, Z. and Chen, Y.-C. and LaCroix, A. and Gordon, R. and Guicherit, O. and Carromeu, C. and Kundu, S. and Lee, E. and Ferrer, M.}, doi = {10.1016/j.slasd.2022.01.003}, journal-iso = {SLAS DISCOV}, journal = {SLAS DISCOVERY}, unique-id = {33289472}, issn = {2472-5552}, year = {2022}, eissn = {2472-5560} } @article{MTMT:32789429, title = {Retroviral infection of human neurospheres and use of stem Cell EVs to repair cellular damage}, url = {https://m2.mtmt.hu/api/publication/32789429}, author = {Branscome, Heather and Khatkar, Pooja and Al, Sharif Sarah and Yin, Dezhong and Jacob, Sheela and Cowen, Maria and Kim, Yuriy and Erickson, James and Brantner, Christine A. and El-Hage, Nazira and Liotta, Lance A. and Kashanchi, Fatah}, doi = {10.1038/s41598-022-05848-x}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {12}, unique-id = {32789429}, issn = {2045-2322}, abstract = {HIV-1 remains an incurable infection that is associated with substantial economic and epidemiologic impacts. HIV-associated neurocognitive disorders (HAND) are commonly linked with HIV-1 infection; despite the development of combination antiretroviral therapy (cART), HAND is still reported to affect at least 50% of HIV-1 infected individuals. It is believed that the over-amplification of inflammatory pathways, along with release of toxic viral proteins from infected cells, are primarily responsible for the neurological damage that is observed in HAND; however, the underlying mechanisms are not well-defined. Therefore, there is an unmet need to develop more physiologically relevant and reliable platforms for studying these pathologies. In recent years, neurospheres derived from induced pluripotent stem cells (iPSCs) have been utilized to model the effects of different neurotropic viruses. Here, we report the generation of neurospheres from iPSC-derived neural progenitor cells (NPCs) and we show that these cultures are permissive to retroviral (e.g. HIV-1, HTLV-1) replication. In addition, we also examine the potential effects of stem cell derived extracellular vesicles (EVs) on HIV-1 damaged cells as there is abundant literature supporting the reparative and regenerative properties of stem cell EVs in the context of various CNS pathologies. Consistent with the literature, our data suggests that stem cell EVs may modulate neuroprotective and anti-inflammatory properties in damaged cells. Collectively, this study demonstrates the feasibility of NPC-derived neurospheres for modeling HIV-1 infection and, subsequently, highlights the potential of stem cell EVs for rescuing cellular damage induced by HIV-1 infection.}, keywords = {CENTRAL-NERVOUS-SYSTEM; neurologic disease; POLYMERASE-CHAIN-REACTION; FIBRILLARY ACIDIC PROTEIN; HIV-1 INFECTION; NEURAL PROGENITOR CELLS; Neurocognitive disorder; LEUKEMIA-LYMPHOMA; REGIONAL SPECIFICATION}, year = {2022}, eissn = {2045-2322} } @article{MTMT:32789469, title = {The spatial self-organization within pluripotent stem cell colonies is continued in detaching aggregates}, url = {https://m2.mtmt.hu/api/publication/32789469}, author = {Elsafi Mabrouk, Mohamed H. and Goetzke, Roman and Abagnale, Giulio and Yesilyurt, Burcu and Salz, Lucia and Cypris, Olivia and Glück, Philipp and Liesenfelder, Sven and Zeevaert, Kira and Ma, Zhiyao and Toledo, Marcelo A.S. and Li, Ronghui and Costa, Ivan G. and Lampert, Angelika and Pachauri, Vivek and Schnakenberg, Uwe and Zenke, Martin and Wagner, Wolfgang}, doi = {10.1016/j.biomaterials.2022.121389}, journal-iso = {BIOMATERIALS}, journal = {BIOMATERIALS}, volume = {282}, unique-id = {32789469}, issn = {0142-9612}, year = {2022}, eissn = {1878-5905}, orcid-numbers = {Yesilyurt, Burcu/0000-0001-5900-5912; Salz, Lucia/0000-0002-4910-7840; Zeevaert, Kira/0000-0002-3062-0310; Toledo, Marcelo A.S./0000-0003-4318-7381; Schnakenberg, Uwe/0000-0002-2251-0605; Zenke, Martin/0000-0002-1107-3251; Wagner, Wolfgang/0000-0002-1971-3217} } @article{MTMT:32696786, title = {Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells}, url = {https://m2.mtmt.hu/api/publication/32696786}, author = {Francistiova, Linda and Vörös, Kinga and Lovász, Zsófia and Dinnyés, András and Kobolák, Julianna}, doi = {10.3389/fnmol.2021.793769}, journal-iso = {FRONT MOL NEUROSCI}, journal = {FRONTIERS IN MOLECULAR NEUROSCIENCE}, volume = {14}, unique-id = {32696786}, issn = {1662-5099}, year = {2022}, eissn = {1662-5099}, orcid-numbers = {Kobolák, Julianna/0000-0002-0986-9517} } @article{MTMT:32789428, title = {Laminin 411 mediates endothelial specification via multiple signaling axes that converge on beta-catenin}, url = {https://m2.mtmt.hu/api/publication/32789428}, author = {Hall, Mikayla L. and Givens, Sophie and Santosh, Natasha and Iacovino, Michelina and Kyba, Michael and Ogle, Brenda M.}, doi = {10.1016/j.stemcr.2022.01.005}, journal-iso = {STEM CELL REP}, journal = {STEM CELL REPORTS}, volume = {17}, unique-id = {32789428}, issn = {2213-6711}, abstract = {The extracellular matrix (ECM) provides essential cues to promote endothelial specification during tissue development in vivo; correspondingly, ECM is considered essential for endothelial differentiation outside of the body. However, systematic studies to assess the precise contribution of individual ECM proteins to endothelial differentiation have not been conducted. Further, the multi-component nature of differentiation protocols makes it challenging to study the underlying mechanisms by which the ECM contributes to cell fate. In this study, we determined that Laminin 411 alone increases endothelial differentiation of induced pluripotent stem cells over collagen I or Matrigel. The effect of ECM was shown to be independent of vascular endothelial growth factor (VEGF) binding capacity. We also show that ECM-guided endothelial differentiation is dependent on activation of focal adhesion kinase (FAK), integrin-linked kinase (ILK), Notch, and beta-catenin pathways. Our results indicate that ECM contributes to endothelial differentiation through multiple avenues, which converge at the expression of active beta-catenin.}, keywords = {PROTEIN-TYROSINE KINASE; GENE-EXPRESSION; GROWTH-FACTOR; EXTRACELLULAR-MATRIX; PROGENITOR CELLS; NOTCH; EMBRYONIC STEM-CELLS; WNT/BETA-CATENIN; Cell & Tissue Engineering; EFFICIENT DIFFERENTIATION}, year = {2022}, eissn = {2213-6711}, pages = {569-583}, orcid-numbers = {Kyba, Michael/0000-0002-5579-7534} } @article{MTMT:32789453, title = {High temporal resolution proteome and phosphoproteome profiling of stem cell-derived hepatocyte development}, url = {https://m2.mtmt.hu/api/publication/32789453}, author = {Krumm, Johannes and Sekine, Keisuke and Samaras, Patroklos and Brazovskaja, Agnieska and Breunig, Markus and Yasui, Ryota and Kleger, Alexander and Taniguchi, Hideki and Wilhelm, Mathias and Treutlein, Barbara and Camp, J. Gray and Kuster, Bernhard}, doi = {10.1016/j.celrep.2022.110604}, journal-iso = {CELL REP}, journal = {CELL REPORTS}, volume = {38}, unique-id = {32789453}, issn = {2211-1247}, year = {2022}, eissn = {2211-1247}, orcid-numbers = {Sekine, Keisuke/0000-0001-5133-0876; Samaras, Patroklos/0000-0001-6042-1585; Brazovskaja, Agnieska/0000-0001-7298-2072; Yasui, Ryota/0000-0002-5088-7696; Treutlein, Barbara/0000-0002-3299-5597} } @article{MTMT:33137059, title = {Progress in Modeling Neural Tube Development and Defects by Organoid Reconstruction}, url = {https://m2.mtmt.hu/api/publication/33137059}, author = {Li, P. and Chen, Y.}, doi = {10.1007/s12264-022-00896-9}, journal-iso = {NEUROSCI BULL}, journal = {NEUROSCIENCE BULLETIN}, volume = {38}, unique-id = {33137059}, issn = {1673-7067}, year = {2022}, eissn = {1995-8218}, pages = {1409-1419} } @{MTMT:34327594, title = {Stem cells, organoids, and cellular therapy}, url = {https://m2.mtmt.hu/api/publication/34327594}, author = {Manfiolli, A.O. and Amaral, R. and Caliari-Oliveira, C.}, booktitle = {Nanotechnology and Regenerative Medicine: History, Techniques, Frontiers, and Applications}, doi = {10.1016/B978-0-323-90471-1.00003-7}, unique-id = {34327594}, year = {2022}, pages = {233-263} } @article{MTMT:33137053, title = {Human Brain Models of Intellectual Disability: Experimental Advances and Novelties}, url = {https://m2.mtmt.hu/api/publication/33137053}, author = {Merckx, N.L.L. and Van, Esch H.}, doi = {10.3390/ijms23126476}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33137053}, issn = {1661-6596}, year = {2022}, eissn = {1422-0067} } @article{MTMT:32616778, title = {Regenerative Neurology and Regenerative Cardiology: Shared Hurdles and Achievements}, url = {https://m2.mtmt.hu/api/publication/32616778}, author = {Mitrečić, Dinko and Hribljan, Valentina and Jagečić, Denis and Isaković, Jasmina and Lamberto, Federica and Horánszky, Alex Lajos and Zana, Melinda and Földes, Gábor and Zavan, Barbara and Pivoriūnas, Augustas and Martinez, Salvador and Mazzini, Letizia and Radenovic, Lidija and Milasin, Jelena and Chachques, Juan Carlos and Buzanska, Leonora and Song, Min Suk and Dinnyés, András}, doi = {10.3390/ijms23020855}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {32616778}, issn = {1661-6596}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Mitrečić, Dinko/0000-0003-4836-1721; Isaković, Jasmina/0000-0001-5971-3142; Lamberto, Federica/0000-0001-9974-1594; Horánszky, Alex Lajos/0000-0001-8456-9787; Zana, Melinda/0000-0001-5725-1300; Földes, Gábor/0000-0001-6348-686X; Zavan, Barbara/0000-0002-4779-4456; Pivoriūnas, Augustas/0000-0001-7009-2535; Milasin, Jelena/0000-0002-6225-7210; Buzanska, Leonora/0000-0003-4433-9906} } @article{MTMT:32696682, title = {An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat}, url = {https://m2.mtmt.hu/api/publication/32696682}, author = {Nunes, Carolina and Singh, Pranika and Mazidi, Zahra and Murphy, Cormac and Bourguignon, Aurore and Wellens, Sara and Chandrasekaran, Vidya and Ghosh, Sreya and Zana, Melinda and Pamies, David and Thomas, Aurélien and Verfaillie, Catherine and Culot, Maxime and Dinnyés, András and Hardy, Barry and Wilmes, Anja and Jennings, Paul and Grillari, Regina and Grillari, Johannes and Zurich, Marie-Gabrielle and Exner, Thomas}, doi = {10.1016/j.tiv.2022.105333}, journal-iso = {TOXICOL IN VITRO}, journal = {TOXICOLOGY IN VITRO}, volume = {81}, unique-id = {32696682}, issn = {0887-2333}, year = {2022}, eissn = {1879-3177} } @article{MTMT:32789460, title = {Upscaling biological complexity to boost neuronal and oligodendroglia maturation and improve in vitro developmental neurotoxicity (DNT) evaluation}, url = {https://m2.mtmt.hu/api/publication/32789460}, author = {Nunes, Carolina and Gorczyca, Gabriela and Mendoza-deGyves, Emilio and Ponti, Jessica and Bogni, Alessia and Carpi, Donatella and Bal-Price, Anna and Pistollato, Francesca}, doi = {10.1016/j.reprotox.2022.03.017}, journal-iso = {REPROD TOXICOL}, journal = {REPRODUCTIVE TOXICOLOGY}, volume = {110}, unique-id = {32789460}, issn = {0890-6238}, year = {2022}, eissn = {1873-1708}, pages = {124-140} } @article{MTMT:33137056, title = {Bioelectric Potential in Next-Generation Organoids: Electrical Stimulation to Enhance 3D Structures of the Central Nervous System}, url = {https://m2.mtmt.hu/api/publication/33137056}, author = {O’Hara-Wright, M. and Mobini, S. and Gonzalez-Cordero, A.}, doi = {10.3389/fcell.2022.901652}, journal-iso = {FRONT CELL DEV BIOL}, journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, volume = {10}, unique-id = {33137056}, issn = {2296-634X}, year = {2022}, eissn = {2296-634X} } @article{MTMT:33703590, title = {Organotypic Cultures of Adult Human Cortex as an Ex vivo Model for Human Stem Cell Transplantation and Validation}, url = {https://m2.mtmt.hu/api/publication/33703590}, author = {Palma-Tortosa, S. and Martínez-Curiel, R. and Aretio-Medina, C. and Avaliani, N. and Kokaia, Z.}, doi = {10.3791/64234}, journal-iso = {JOVE-J VIS EXP}, journal = {JOVE-JOURNAL OF VISUALIZED EXPERIMENTS}, volume = {2022}, unique-id = {33703590}, issn = {1940-087X}, year = {2022}, eissn = {1940-087X} } @article{MTMT:32957710, title = {Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids}, url = {https://m2.mtmt.hu/api/publication/32957710}, author = {Romero-Morales, A.I. and Gama, V.}, doi = {10.3389/fnmol.2022.840265}, journal-iso = {FRONT MOL NEUROSCI}, journal = {FRONTIERS IN MOLECULAR NEUROSCIENCE}, volume = {15}, unique-id = {32957710}, issn = {1662-5099}, abstract = {Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids. Copyright © 2022 Romero-Morales and Gama.}, keywords = {NEURITE OUTGROWTH; APOPTOSIS; PHENOTYPE; signal transduction; BONE MORPHOGENETIC PROTEIN; Stem Cells; review; human; Cell Survival; Cell Differentiation; retinoic acid; Nerve Degeneration; Mitochondria; cell proliferation; synaptic transmission; glial fibrillary acidic protein; Gene Expression; machine learning; triacylglycerol; cell migration; mitochondrion; MORPHOGENESIS; cell expansion; follow up; microRNA; apolipoprotein E; personalized medicine; upregulation; brain derived neurotrophic factor; HYPOXIA; MITOCHONDRIAL BIOGENESIS; Glycolysis; Glycolysis; Bioenergy; ASTROCYTE; diencephalon; genetic transfection; fibroblast growth factor; nerve cell differentiation; mitochondrial membrane potential; hyperpolarization; nervous system development; brain size; hypoxia inducible factor 1alpha; OLIGODENDROGLIA; Regenerative Medicine; Notch receptor; Notch signaling; Motor Neuron Disease; myelination; oxidative phosphorylation; oxidative phosphorylation; pluripotent stem cell; GASTRULATION; induced pluripotent stem cell; nuclear reprogramming; hereditary motor sensory neuropathy; epithelial mesenchymal transition; sonic hedgehog protein; Mouse embryonic stem cell; transcription factor PAX6; mitochondrial dynamics; Whole exome sequencing; transcription factor Sox2; Gene editing; oxidative phosphorylation uncoupling; neural precursor cells; neural rosettes; cerebral organoid; brain organoids}, year = {2022}, eissn = {1662-5099} } @article{MTMT:33341431, title = {Human iPSC-derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis}, url = {https://m2.mtmt.hu/api/publication/33341431}, author = {Romero-Morales, Alejandra I. and Robertson, Gabriella L. and Rastogi, Anuj and Rasmussen, Megan L. and Temuri, Hoor and McElroy, Gregory Scott and Chakrabarty, Ram Prosad and Hsu, Lawrence and Almonacid, Paula M. and Millis, Bryan A. and Chandel, Navdeep S. and Cartailler, Jean-Philippe and Gama, Vivian}, doi = {10.1242/dev.199914}, journal-iso = {DEVELOPMENT}, journal = {DEVELOPMENT}, volume = {149}, unique-id = {33341431}, issn = {0950-1991}, abstract = {Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated human induced pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines. Using whole-exome and mitochondrial sequencing, we identified unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines were viable and capable of differentiating into progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS patient-derived cerebral organoids showed defects in neural epithelial bud generation, size and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural precursor cells with abnormal mitochondrial morphology, characterized by fragmentation and disorganization, and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient -derived cell lines that can be used to study Leigh syndrome.}, keywords = {Stem Cells; Mitochondria; Glycolysis; oxidative phosphorylation; Leigh Syndrome; neural precursor cells; neural rosettes; brain organoids}, year = {2022}, eissn = {1477-9129}, orcid-numbers = {Cartailler, Jean-Philippe/0000-0002-0312-2391} } @article{MTMT:32789430, title = {Tissue-Specific Hydrogels for Three-Dimensional Printing and Potential Application in Peripheral Nerve Regeneration}, url = {https://m2.mtmt.hu/api/publication/32789430}, author = {Wang, Tao and Han, Yang and Wu, Zejia and Qiu, Shuai and Rao, Zilong and Zhao, Cailing and Zhu, Qingtang and Quan, Daping and Bai, Ying and Liu, Xiaolin}, doi = {10.1089/ten.tea.2021.0093}, journal-iso = {TISSUE ENG PT A}, journal = {TISSUE ENGINEERING PART A}, volume = {28}, unique-id = {32789430}, issn = {1937-3341}, abstract = {Impact statementTissue-derived decellularized matrices have drawn broad interests for their versatile applications in tissue engineering and regenerative medicine, especially the decellularized peripheral nerve matrix, which can effectively facilitate axonal extension, remyelination, and neural functional restoration after peripheral nerve injury. However, neither decellularized porcine nerve matrix (pDNM) nor pDNM hydrogel (pDNM-G) can be directly used in three-dimensional printing for personalized nerve constructs or cell transplantation. This work developed a hybrid hydrogel consisting of decellularized extracellular matrix hydrogel (dECM-G) and photocrosslinkable gelatin methacrylate (GelMA), which resulted in significantly improved printability and structural fidelity. The GelMA/pDNM-G hydrogel retained high bioactivity and tissue-specificity due to its dECM-G content. Such hybrid hydrogel systems built up a springboard in advanced biomaterials for neural tissue engineering, as well as a promising strategy for dECM containing bioprinting. Decellularized extracellular matrix hydrogel (dECM-G) has demonstrated its significant tissue-specificity, high biocompatibility, and versatile utilities in tissue engineering. However, the low mechanical stability and fast degradation are major drawbacks for its application in three-dimensional (3D) printing. Herein, we report a hybrid hydrogel system consisting of dECM-Gs and photocrosslinkable gelatin methacrylate (GelMA), which resulted in significantly improved printability and structural fidelity. These premixed hydrogels retained high bioactivity and tissue-specificity due to their containing dECM-Gs. More specifically, it was realized that the hydrogel containing dECM-G derived from porcine peripheral nerves (GelMA/pDNM-G) effectively facilitated neurite growth and Schwann cell migration from two-dimensional cultured dorsal root ganglion explants. The nerve cells were also encapsulated in the GelMA/pDNM-G hydrogel for 3D culture or underwent cell-laden bioprinting with high cell viability. The preparation of such GelMA/dECM-G hydrogels enabled the recapitulation of functional tissues through extrusion-based bioprinting, which holds great potential for applications in regenerative medicine.}, keywords = {GENERATION; SCAFFOLDS; CELL BIOLOGY; tissue specificity; neurite; Cell & Tissue Engineering; Engineering, Biomedical; 3D bioprinting; decellularized extracellular matrix hydrogel}, year = {2022}, eissn = {1937-335X}, pages = {161-174} } @{MTMT:32789437, title = {Toward Understanding Neurodegeneration Using Brain Organoids}, url = {https://m2.mtmt.hu/api/publication/32789437}, author = {Wongtrakoongate, Patompon and Pakiranay, Chatbenja and Kitiyanant, Narisorn}, booktitle = {Organoid Technology for Disease Modelling and Personalized Treatment}, doi = {10.1007/978-3-030-93056-1_5}, unique-id = {32789437}, year = {2022}, pages = {91-107} } @article{MTMT:32287697, title = {Patient-derived iPSCs, a reliable in vitro model for the investigation of Alzheimer's disease}, url = {https://m2.mtmt.hu/api/publication/32287697}, author = {Amponsah, Asiamah Ernest and Guo, Ruiyun and Kong, Desheng and Feng, Baofeng and He, Jingjing and Zhang, Wei and Liu, Xin and Du, Xiaofeng and Ma, Zhenhuan and Liu, Boxin and Ma, Jun and Cui, Huixian}, doi = {10.1515/revneuro-2020-0065}, journal-iso = {REV NEUROSCI}, journal = {REVIEWS IN THE NEUROSCIENCES}, volume = {32}, unique-id = {32287697}, issn = {0334-1763}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease and a common cause of dementia among elderly individuals. The disease is characterized by progressive cognitive decline, accumulation of senile amyloid plaques and neurofibrillary tangles, oxidative stress, and inflammation. Human-derived cell models of AD are scarce, and over the years, non-human-derived models have been developed to recapitulate clinical AD, investigate the disease's pathogenesis and develop therapies for the disease. Several pharmacological compounds have been developed for AD based on findings from non-human-derived cell models; however, these pharmacological compounds have failed at different phases of clinical trials. This necessitates the application of human-derived cell models, such as induced pluripotent stem cells (iPSCs) in their optimized form in AD mechanistic studies and preclinical drug testing. This review provides an overview of AD and iPSCs. The AD-relevant phenotypes of iPSC-derived AD brain cells and the usefulness of iPSCs in AD are highlighted. Finally, the various recommendations that have been made to enhance iPSC/AD modelling are discussed.}, keywords = {AMYLOID-BETA; TAU; Reprogramming; IPSC; Alzheimer’s; integrating; Non-integrating; Oxidative stress}, year = {2021}, eissn = {2191-0200}, pages = {379-402} } @article{MTMT:32287695, title = {A protein-centric view of in vitro biological model systems for schizophrenia}, url = {https://m2.mtmt.hu/api/publication/32287695}, author = {Chandrasekaran, Abinaya and Jensen, Pia and Mohamed, Fadumo A. and Lancaster, Madeline and Benros, Michael E. and Larsen, Martin R. and Freude, Kristine K.}, doi = {10.1002/stem.3447}, journal-iso = {STEM CELLS}, journal = {STEM CELLS}, volume = {39}, unique-id = {32287695}, issn = {1066-5099}, abstract = {Schizophrenia (SCZ) is a severe brain disorder, characterized by psychotic, negative, and cognitive symptoms, affecting 1% of the population worldwide. The precise etiology of SCZ is still unknown; however, SCZ has a high heritability, and is associated with genetic, environmental, and social risk factors. Even though the genetic contribution is indisputable, the discrepancies between transcriptomics and proteomics in brain tissues are consistently challenging the field to decipher the disease pathology. Here we provide an overview of the state of the art of neuronal two-dimensional and three-dimensional model systems that can be combined with proteomics analyses to decipher specific brain pathology and detection of alternative entry points for drug development.}, keywords = {Tissue Engineering; Induced pluripotent stem cells; experimental models; neural differentiation}, year = {2021}, eissn = {1549-4918}, pages = {1569-1578} } @article{MTMT:31882108, title = {Chitosan 3D cell culture system promotes naive-like features of human induced pluripotent stem cells: A novel tool to sustain pluripotency and facilitate differentiation}, url = {https://m2.mtmt.hu/api/publication/31882108}, author = {Chang, Po-Hsiang and Chao, Hsiao-Mei and Chern, Edward and Hsu, Shan-hui}, doi = {10.1016/j.biomaterials.2020.120575}, journal-iso = {BIOMATERIALS}, journal = {BIOMATERIALS}, volume = {268}, unique-id = {31882108}, issn = {0142-9612}, abstract = {A simplified and cost-effective culture system for maintaining the pluripotency of human induced pluripotent stem cells (hiPSCs) is crucial for stem cell applications. Although recombinant protein-based feeder-free hiPSC culture systems have been developed, their manufacturing processes are expensive and complicated, which hinders hiPSC technology progress. Chitosan, a versatile biocompatible polysaccharide, has been reported as a biomaterial for three-dimensional (3D) cell culture system that promotes the physiological activities of mesenchymal stem cells and cancer cells. In the current study, we demonstrated that chitosan membranes sustained proliferation and pluripotency of hiPSCs in long-term culture (up to 365 days). Moreover, using vitronectin as the comparison group, the pluripotency of hiPSCs grown on the membranes was altered into a naive-like state, which, for pluripotent stem cells, is an earlier developmental stage with higher stemness. On the chitosan membranes, hiPSCs self-assembled into 3D spheroids with an average diameter of similar to 100 mu m. These hiPSC spheroids could be directly differentiated into lineage-specific cells from the three germ layers with 3D structures. Collectively, chitosan membranes not only promoted the naive pluripotent features of hiPSCs but also provided a novel 3D differentiation platform. This convenient biomaterial-based culture system may enable the effective expansion and accessibility of hiPSCs for regenerative medicine, disease modeling, and drug screening.}, year = {2021}, eissn = {1878-5905}, orcid-numbers = {Chern, Edward/0000-0002-9317-5410} } @article{MTMT:32287692, title = {May the Force Be with You (Or Not): The Immune System under Microgravity}, url = {https://m2.mtmt.hu/api/publication/32287692}, author = {ElGindi, Mei and Sapudom, Jiranuwat and Ibrahim, Ibrahim Hamed and Al-Sayegh, Mohamed and Chen, Weiqiang and Garcia-Sabate, Anna and Teo, Jeremy C. M.}, doi = {10.3390/cells10081941}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {10}, unique-id = {32287692}, abstract = {All terrestrial organisms have evolved and adapted to thrive under Earth's gravitational force. Due to the increase of crewed space flights in recent years, it is vital to understand how the lack of gravitational forces affects organisms. It is known that astronauts who have been exposed to microgravity suffer from an array of pathological conditions including an impaired immune system, which is one of the most negatively affected by microgravity. However, at the cellular level a gap in knowledge exists, limiting our ability to understand immune impairment in space. This review highlights the most significant work done over the past 10 years detailing the effects of microgravity on cellular aspects of the immune system.}, keywords = {immunology; Microgravity; immune cells; Space research; mechanotransduction; space biology}, year = {2021}, eissn = {2073-4409}, orcid-numbers = {Sapudom, Jiranuwat/0000-0001-6627-7713; Al-Sayegh, Mohamed/0000-0003-3865-1688; Garcia-Sabate, Anna/0000-0001-8959-9002} } @article{MTMT:32468380, title = {Optimal culture conditions for neurosphere formation and neuronal differentiation from human dental pulp stem cells}, url = {https://m2.mtmt.hu/api/publication/32468380}, author = {Gonmanee, Thanasup and Arayapisit, Tawepong and Vongsavan, Kutkao and Phruksaniyom, Chareerut and Sritanaudomchai, Hathaitip}, doi = {10.1590/1678-7757-2021-0296}, journal-iso = {J APPL ORAL SCI}, journal = {JOURNAL OF APPLIED ORAL SCIENCE}, volume = {29}, unique-id = {32468380}, issn = {1678-7757}, abstract = {Objectives: Human dental pulp stem cells (DPSCs) have been used to regenerate damaged nervous tissues. However, the methods of committing DPSCs into neural stem/progenitor cells (NSPCs) or neurospheres are highly diverse, resulting in many neuronal differentiation outcomes. This study aims to validate an optimal protocol for inducing DPSCs into neurospheres and neurons. Methodology: After isolation and characterization of mesenchymal stem cell identity, DPSCs were cultured in a NSPC induction medium and culture vessels. The durations of the culture, dissociation methods, and passage numbers of DPSCs were varied. Results: Neurosphere formation requires a special surface that inhibits cell attachment. Five-days was the most appropriate duration for generating proliferative neurospheres and they strongly expressed Nestin, an NSPC marker. Neurosphere reformation after being dissociated by the Accutase enzyme was significantly higher than other methods. Passage number of DPSCs did not affect neurosphere formation, but did influence neuronal differentiation. We found that the cells expressing a neuronal marker, beta-tubulin III, and exhibiting neuronal morphology were significantly higher in the early passage of the DPSCs. Conclusion: These results suggest a guideline to obtain a high efficiency of neurospheres and neuronal differentiation from DPSCs for further study and neurodegeneration therapeutics.}, keywords = {IN-VITRO; GENERATION; Cell Culture Techniques; neurotrophins; NEURONAL DIFFERENTIATION; Mesenchymal Stem Cells; NEURAL INDUCTION}, year = {2021}, eissn = {1678-7765} } @article{MTMT:31467828, title = {Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells}, url = {https://m2.mtmt.hu/api/publication/31467828}, author = {Heuer, Rachel A. and Nella, Kevin T. and Chang, Hsiang-Tsun and Coots, Kyle S. and Oleksijew, Andrew M. and Roque, Christian B. and Silva, Luisa H. A. and McGuire, Tammy L. and Homma, Kazuaki and Matsuoka, Akihiro J.}, doi = {10.1089/ten.tea.2020.0078}, journal-iso = {TISSUE ENG PT A}, journal = {TISSUE ENGINEERING PART A}, volume = {27}, unique-id = {31467828}, issn = {1937-3341}, abstract = {Stem cell-replacement therapies have been proposed as a potential tool to treat sensorineural hearing loss by aiding the regeneration of spiral ganglion neurons (SGNs) in the inner ear. However, transplantation procedures have yet to be explored thoroughly to ensure proper cell differentiation and optimal transplant procedures. We hypothesized that the aggregation of human embryonic stem cell (hESC)-derived otic neuronal progenitor (ONP) cells into a multicellular form would improve their function and their survivalin vivopost-transplantation. We generated hESC-derived ONP spheroids-an aggregate form conducive to differentiation, transplantation, and prolonged cell survival-to optimize conditions for their transplantation. Our findings indicate that these cell spheroids maintain the molecular and functional characteristics similar to those of ONP cells, which are upstream in the SGN lineage. Moreover, our phenotypical, electrophysiological, and mechanical data suggest an optimal spheroid transplantation point after 7 days ofin vitrothree-dimensional (3D) culture. We have also developed a feasible transplantation protocol for these spheroids using a micropipette aided by a digital microinjection system. In summary, the present work demonstrates that the transplantation of ONP cells in spheroid form into the inner ear through micropipette 7 days after seeding for 3D spheroid culture is an expedient and viable method for stem cell replacement therapies in the inner ear.Impact statement Sensorineural hearing loss affects millions of people worldwide. Although inner ear stem cell replacement therapies offer a promising method to mitigate this hearing loss by aiding in the regeneration of spiral ganglion neurons, fewin vivostudies have been performed in this area. By providing detailed cell spheroid characterization, determining an optimal development stage for transplantation, and establishing a reliable and reproducible transplantation protocol, we aimed to provide the necessary details to bridge the gap betweenin vitroexperiments andin vivostudies of stem cell replacement therapies in the inner ear.}, keywords = {Stem Cell Niche; inner ear; Human embryonic stem cells; Spheroid; three-dimensional culture; Spiral ganglion neurons; stem cell replacement therapy}, year = {2021}, eissn = {1937-335X}, pages = {256-269} } @article{MTMT:32287690, title = {Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p-CaMKII/ERK/CREB and ox-CaMKII-Dependent MAPK/NF-kappa B Pathways}, url = {https://m2.mtmt.hu/api/publication/32287690}, author = {Jiang, Hailun and Ashraf, Ghulam Md and Liu, Mimin and Zhao, Kaiyue and Wang, Yu and Wang, Linlin and Xing, Jianguo and Alghamdi, Badrah S. and Li, Zhuorong and Liu, Rui}, doi = {10.1155/2021/6673967}, journal-iso = {OXID MED CELL LONGEV}, journal = {OXIDATIVE MEDICINE AND CELLULAR LONGEVITY}, volume = {2021}, unique-id = {32287690}, issn = {1942-0900}, abstract = {Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-kappa B associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKII alpha siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKII alpha. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.}, year = {2021}, eissn = {1942-0994} } @article{MTMT:32287696, title = {Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation}, url = {https://m2.mtmt.hu/api/publication/32287696}, author = {Mollo, Nunzia and Esposito, Matteo and Aurilia, Miriam and Scognamiglio, Roberta and Accarino, Rossella and Bonfiglio, Ferdinando and Cicatiello, Rita and Charalambous, Maria and Procaccini, Claudio and Micillo, Teresa and Genesio, Rita and Cali, Gaetano and Secondo, Agnese and Paladino, Simona and Matarese, Giuseppe and De Vita, Gabriella and Conti, Anna and Nitsch, Lucio and Izzo, Antonella}, doi = {10.3390/biology10070609}, journal-iso = {BIOLOGY-BASEL}, journal = {BIOLOGY-BASEL}, volume = {10}, unique-id = {32287696}, abstract = {Simple Summary Down Syndrome, which is due to the presence of three copies of chromosome 21, always presents with mental retardation, possibly caused by defects in the development of neurons. In recent years, it has been shown that cells and tissues in Down syndrome manifest alterations in the function of mitochondria, the organelles that provide energy to cells. We hypothesized that mitochondrial dysfunction might contribute to the defect in neuronal cell development. To test this hypothesis, we generated a model of stem cells that, upon specific treatments, are capable of giving rise to neuronal cells, as evidenced by the synthesis of specific proteins. We observed that stem cells derived from Down syndrome individuals, after 21 days of growth in an artificial system, had an abnormal tendency to develop as glial cells, compared with control cells. As early as day 7 of culture, the trisomic cells also exhibited defects in mitochondrial function, such as anomalies in their calcium level, oxygen free radicals, oxygen consumption, and synthesis of ATP, a molecule that is critical in energy conversions. These results indicate that alterations in neuronal development and mitochondrial function occur early in this model, which we think is suitable for answering further questions. Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.}, keywords = {mitochondrial dysfunction; down syndrome; Induced pluripotent stem cells; neural differentiation}, year = {2021}, eissn = {2079-7737}, orcid-numbers = {Bonfiglio, Ferdinando/0000-0003-2488-3867; Paladino, Simona/0000-0001-5332-6774; Matarese, Giuseppe/0000-0001-9429-0616; De Vita, Gabriella/0000-0002-7302-1174; Conti, Anna/0000-0002-2054-7375} } @mastersthesis{MTMT:32789450, title = {Identification of CUL9-Related Signaling Pathways in Human Pluripotent Stem Cells and Cortical Precursors}, url = {https://m2.mtmt.hu/api/publication/32789450}, author = {Natalya, Anne Ortolano}, unique-id = {32789450}, year = {2021} } @article{MTMT:32287698, title = {A proteomics approach for the identification of cullin-9 (CUL9) related signaling pathways in induced pluripotent stem cell models}, url = {https://m2.mtmt.hu/api/publication/32287698}, author = {Ortolano, Natalya A. and Romero-Morales, Alejandra I and Rasmussen, Megan L. and Bodnya, Caroline and Kline, Leigh A. and Joshi, Piyush and Connelly, Jon P. and Rose, Kristie L. and Pruett-Miller, Shondra M. and Gama, Vivian}, doi = {10.1371/journal.pone.0248000}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {16}, unique-id = {32287698}, issn = {1932-6203}, abstract = {CUL9 is a non-canonical and poorly characterized member of the largest family of E3 ubiquitin ligases known as the Cullin RING ligases (CRLs). Most CRLs play a critical role in developmental processes, however, the role of CUL9 in neuronal development remains elusive. We determined that deletion or depletion of CUL9 protein causes aberrant formation of neural rosettes, an in vitro model of early neuralization. In this study, we applied mass spectrometric approaches in human pluripotent stem cells (hPSCs) and neural progenitor cells (hNPCs) to identify CUL9 related signaling pathways that may contribute to this phenotype. Through LC-MS/MS analysis of immunoprecipitated endogenous CUL9, we identified several subunits of the APC/C, a major cell cycle regulator, as potential CUL9 interacting proteins. Knockdown of the APC/C adapter protein FZR1 resulted in a significant increase in CUL9 protein levels, however, CUL9 does not appear to affect protein abundance of APC/C subunits and adapters or alter cell cycle progression. Quantitative proteomic analysis of CUL9 KO hPSCs and hNPCs identified protein networks related to metabolic, ubiquitin degradation, and transcriptional regulation pathways that are disrupted by CUL9 deletion in both hPSCs. No significant changes in oxygen consumption rates or ATP production were detected in either cell type. The results of our study build on current evidence that CUL9 may have unique functions in different cell types and that compensatory mechanisms may contribute to the difficulty of identifying CUL9 substrates.}, year = {2021}, eissn = {1932-6203}, orcid-numbers = {Gama, Vivian/0000-0002-1201-1394} } @article{MTMT:31882241, title = {Comparative Analysis of Chemotherapy-Induced Peripheral Neuropathy in Bioengineered Sensory Nerve Tissue Distinguishes Mechanistic Differences in Early-Stage Vincristine-, Cisplatin-, and Paclitaxel-Induced Nerve Damage}, url = {https://m2.mtmt.hu/api/publication/31882241}, author = {Pollard, Kevin J and Bolon, Brad and Moore, Michael J}, doi = {10.1093/toxsci/kfaa186}, journal-iso = {TOXICOL SCI}, journal = {TOXICOLOGICAL SCIENCES}, volume = {180}, unique-id = {31882241}, issn = {1096-6080}, year = {2021}, eissn = {1096-0929}, pages = {76-88}, orcid-numbers = {Pollard, Kevin J/0000-0002-8503-0393; Bolon, Brad/0000-0002-6065-1492; Moore, Michael J/0000-0002-7853-5756} } @article{MTMT:32287694, title = {Morphine-sensitive synaptic transmission emerges in embryonic rat microphysiological model of lower afferent nociceptive signaling}, url = {https://m2.mtmt.hu/api/publication/32287694}, author = {Pollard, Kevin J. and Bowser, Devon A. and Anderson, Wesley A. and Meselhe, Mostafa and Moore, Michael J.}, doi = {10.1126/sciadv.abj2899}, journal-iso = {SCI ADV}, journal = {SCIENCE ADVANCES}, volume = {7}, unique-id = {32287694}, issn = {2375-2548}, abstract = {Debilitating chronic pain resulting from genetic predisposition, injury, or acquired neuropathy is becoming increasingly pervasive. Opioid analgesics remain the gold standard for intractable pain, but overprescription of increasingly powerful and addictive opioids has contributed to the current prescription drug abuse epidemic. There is a pressing need to screen experimental compounds more efficiently for analgesic potential that remains unmet by conventional research models. The spinal cord dorsal horn is a common target for analgesic intervention, where peripheral nociceptive signals are relayed to the central nervous system through synaptic transmission. Here, we demonstrate that coculturing peripheral and dorsal spinal cord nerve cells in a novel bioengineered microphysiological system facilitates self-directed emergence of native nerve tissue macrostructure and concerted synaptic function. The mechanistically distinct analgesics-morphine, lidocaine, and clonidine- differentially and predictably modulate this microphysiological synaptic transmission. Screening drug candidates for similar microphysiological profiles will efficiently identify therapeutics with analgesic potential.}, year = {2021}, eissn = {2375-2548}, orcid-numbers = {Meselhe, Mostafa/0000-0002-8832-8451} } @article{MTMT:32287691, title = {Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease}, url = {https://m2.mtmt.hu/api/publication/32287691}, author = {Salcedo, Claudia and Wagner, Antonie and Andersen, Jens V. and Vinten, Kasper Tore and Waagepetersen, Helle S. and Schousboe, Arne and Freude, Kristine K. and Aldana, Blanca I.}, doi = {10.1007/s11064-021-03276-3}, journal-iso = {NEUROCHEM RES}, journal = {NEUROCHEMICAL RESEARCH}, volume = {46}, unique-id = {32287691}, issn = {0364-3190}, abstract = {Alterations in neurotransmitter homeostasis, primarily of glutamate and GABA, is strongly implicated in the pathophysiology of Alzheimer's disease (AD). Homeostasis at the synapse is maintained by neurotransmitter recycling between neurons and astrocytes. Astrocytes support neuronal transmission through glutamine synthesis, which can be derived from oxidative metabolism of GABA. However, the precise implications of astrocytic GABA metabolism in AD remains elusive. The aim of this study was to investigate astrocytic GABA metabolism in AD pathology implementing human induced pluripotent stem cells derived astrocytes. Metabolic mapping of GABA was performed with [U-C-13]GABA stable isotopic labeling using gas chromatography coupled to mass spectrometry (GC-MS). Neurotransmitter and amino acid content was quantified via high performance liquid chromatography (HPLC) and protein expression was investigated by Western blot assay. Cell lines carrying mutations in either amyloid precursor protein (APP) or presenilin1 (PSEN-1) were used as AD models and were compared to a control cell line of the same genetic background. AD astrocytes displayed a reduced oxidative GABA metabolism mediated by a decreased uptake capacity of GABA, as GABA transporter 3 (GAT3) was downregulated in AD astrocytes compared to the controls. Interestingly, the carbon backbone of GABA in AD astrocytes was utilized to a larger extent to support glutamine synthesis compared to control astrocytes. The results strongly indicate alterations in GABA uptake and metabolism in AD astrocytes linked to reduced GABA transporter expression, hereby contributing further to neurotransmitter disturbances.}, keywords = {glutamate; glutamine; energy metabolism; APP; GAT3; PSEN-1}, year = {2021}, eissn = {1573-6903}, pages = {2676-2686}, orcid-numbers = {Schousboe, Arne/0000-0001-9600-402X} } @article{MTMT:32468477, title = {Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease}, url = {https://m2.mtmt.hu/api/publication/32468477}, author = {Salcedo, Claudia and Andersen, Jens V. and Vinten, Kasper Tore and Pinborg, Lars H. and Waagepetersen, Helle S. and Freude, Kristine K. and Aldana, Blanca I.}, doi = {10.3389/fnagi.2021.736580}, journal-iso = {FRONT AGING NEUROSCI}, journal = {FRONTIERS IN AGING NEUROSCIENCE}, volume = {13}, unique-id = {32468477}, issn = {1663-4365}, year = {2021}, eissn = {1663-4365} } @{MTMT:34779263, title = {Human induced pluripotent stem cell–derived astrocytes progenitors as discovery platforms: opportunities and challenges}, url = {https://m2.mtmt.hu/api/publication/34779263}, author = {Taga, A. and Maragakis, N.J.}, booktitle = {iPSC Derived Progenitors}, doi = {10.1016/B978-0-323-85545-7.00005-3}, unique-id = {34779263}, year = {2021}, pages = {45-89} } @article{MTMT:32468379, title = {Establishment of an Electrophysiological Platform for Modeling ALS with Regionally-Specific Human Pluripotent Stem Cell-Derived Astrocytes and Neurons}, url = {https://m2.mtmt.hu/api/publication/32468379}, author = {Taga, Arens and Habela, Christa W. and Johns, Alexandra and Liu, Shiyu and O'Brien, Mollie and Maragakis, Nicholas J.}, doi = {10.3791/62726}, journal-iso = {JOVE-J VIS EXP}, journal = {JOVE-JOURNAL OF VISUALIZED EXPERIMENTS}, unique-id = {32468379}, issn = {1940-087X}, abstract = {Human pluripotent stem cell-derived astrocytes (hiPSC-A) and neurons (hiPSCN) provide a powerful tool for modeling Amyotrophic Lateral Sclerosis (ALS) pathophysiology in vitro. Multi-electrode array (MEA) recordings are a means to record electrical field potentials from large populations of neurons and analyze network activity over time. It was previously demonstrated that the presence of hiPSC-A that are differentiated using techniques to promote a spinal cord astrocyte phenotype improved maturation and electrophysiological activity of regionally specific spinal cord hiPSC-motor neurons (MN) when compared to those cultured without hiPSCA or in the presence of rodent astrocytes. Described here is a method to co-culture spinal cord hiPSC-A with hiPSC-MN and record electrophysiological activity using MEA recordings. While the differentiation protocols described here are particular to astrocytes and neurons that are regionally specific to the spinal cord, the co-culturing platform can be applied to astrocytes and neurons differentiated with techniques specific to other fates, including cortical hiPSC-A and hiPSC-N. These protocols aim to provide an electrophysiological assay to inform about glia-neuron interactions and provide a platform for testing drugs with therapeutic potential in ALS.}, year = {2021}, eissn = {1940-087X} } @article{MTMT:31882110, title = {Valproic Acid Labeled Chitosan Nanoparticles Promote the Proliferation and Differentiation of Neural Stem Cells After Spinal Cord Injury}, url = {https://m2.mtmt.hu/api/publication/31882110}, author = {Wang, Dimin and Wang, Kai and Liu, Zhenlei and Wang, Zonglin and Wu, Hao}, doi = {10.1007/s12640-020-00304-y}, journal-iso = {NEUROTOX RES}, journal = {NEUROTOXICITY RESEARCH}, volume = {39}, unique-id = {31882110}, issn = {1029-8428}, abstract = {Chitosan nanoparticles and valproic acid are demonstrated as the protective agents in the treatment of spinal cord injury (SCI). However, the effects of valproic acid-labeled chitosan nanoparticles (VA-CN) on endogenous spinal cord neural stem cells (NSCs) following SCI and the underlying mechanisms involved remain to be elucidated. In this study, the VA-CN was constructed and the effects of VA-CN on NSCs were assessed in a rat model of SCI. We found VA-CN treatment promoted recovery of the tissue and locomotive function following SCI. Moreover, administration of VA-CN significantly enhanced neural stem cell proliferation and the expression levels of neurotrophic factors following SCI. Furthermore, administration of VA-CN led to a decrease in the number of microglia following SCI. In addition, VA-CN treatment significantly increased the Tuj 1- positive cells in the spinal cord of the SCI rats, suggesting that VA-CN could enhance the differentiation of NSCs following SCI. In conclusion, these results demonstrated that VA-CN could improve the functional and histological recovery through promoting the proliferation and differentiation of NSCs following SCI, which would provide a newly potential therapeutic manner for the treatment of SCI.}, year = {2021}, eissn = {1476-3524}, pages = {456-466} } @article{MTMT:31685840, title = {Multiplexed analysis of neural cytokine signaling by a novel neural cell-cell interaction microchip}, url = {https://m2.mtmt.hu/api/publication/31685840}, author = {Abdullah, Mohammed A. A. and Amini, Nooshin and Yang, Liwei and Paluh, Janet L. and Wang, Jun}, doi = {10.1039/d0lc00401d}, journal-iso = {LAB CHIP}, journal = {LAB ON A CHIP}, volume = {20}, unique-id = {31685840}, issn = {1473-0197}, abstract = {Multipotent neural stem cells (NSCs) are widely applied in pre-clinical and clinical trials as a cell source to promote tissue regeneration in neurodegenerative diseases. Frequently delivered as dissociated cells, aggregates or self-organized rosettes, it is unknown whether disruption of the NSC rosette morphology or method of formation affect signaling profiles of these cells that may impact uniformity of outcomes in cell therapies. Here we generate a neural cell-cell interaction microchip (NCCIM) as an in vitro platform to simultaneously track an informed panel of cytokines and co-evaluate cell morphology and biomarker expression coupled to a sandwich ELISA platform. We apply multiplex in situ tagging technology (MIST) to evaluate ten cytokines (PDGF-AA, GDNF, BDNF, IGF-1, FGF-2, IL-6, BMP-4, CNTF, beta-NGF, NT-3) on microchips for EB-derived rosettes, single cell dissociated rosettes and reformed rosette neurospheres. Of the cytokines evaluated, EB-derived rosettes secrete PDGF-AA, GDNF and FGF-2 prominently, whereas this profile is temporarily lost upon dissociation to single cells and in reformed neurospheres two additional cytokines, BDNF and beta-NGF, are also secreted. This study on NSC rosettes demonstrates the development, versatility and utility of the NCCIM as a sensitive multiplex detector of cytokine signaling in a high throughput and controlled microenvironment. The NCCIM is expected to provide important new information to refine cell source choices in therapies as well as to support development of informative 2D or 3D in vitro models including areas of neurodegeneration or neuroplasticity.}, year = {2020}, eissn = {1473-0189}, pages = {3980-3995}, orcid-numbers = {Abdullah, Mohammed A. A./0000-0002-7790-0205; Wang, Jun/0000-0002-3097-1006} } @mastersthesis{MTMT:32468444, title = {Development of human induced pluripotent stem cell-derived neural cultures for seizure-liability testing}, url = {https://m2.mtmt.hu/api/publication/32468444}, author = {Alastair, Grainger}, unique-id = {32468444}, year = {2020} } @article{MTMT:31391465, title = {Generating homogenous cortical preplate and deep-layer neurons using a combination of 2D and 3D differentiation cultures}, url = {https://m2.mtmt.hu/api/publication/31391465}, author = {Alsanie, Walaa F. and Bahri, Ola A. and Habeeballah, Hamza H. and Alhomrani, Majid and Almehmadi, Mazen M. and Alsharif, Khalaf and Felemban, Ebaa M. and Althobaiti, Yusuf S. and Almalki, Atiah H. and Alsaab, Hashem O. and Gaber, Ahmed and Hassan, Mohamed M. and Hardy, Ana Maria Gregio and Alhadidi, Qasim}, doi = {10.1038/s41598-020-62925-9}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {10}, unique-id = {31391465}, issn = {2045-2322}, year = {2020}, eissn = {2045-2322} } @article{MTMT:31467830, title = {An engineered three-dimensional stem cell niche in the inner ear by applying a nanofibrillar cellulose hydrogel with a sustained-release neurotrophic factor delivery system}, url = {https://m2.mtmt.hu/api/publication/31467830}, author = {Chang, Hsiang-Tsun and Heuer, Rachel A. and Oleksijew, Andrew M. and Coots, Kyle S. and Roque, Christian B. and Nella, Kevin T. and McGuire, Tammy L. and Matsuoka, Akihiro J.}, doi = {10.1016/j.actbio.2020.03.007}, journal-iso = {ACTA BIOMATER}, journal = {ACTA BIOMATERIALIA}, volume = {108}, unique-id = {31467830}, issn = {1742-7061}, abstract = {Although the application of human embryonic stem cells (hESCs) in stem cell-replacement therapy remains promising, its potential is hindered by a low cell survival rate in post-transplantation within the inner ear. Here, we aim to enhance the in vitro and in vivo survival rate and neuronal differentiation of otic neuronal progenitors (ONPs) by generating an artificial stem cell niche consisting of three-dimensional (3D) hESC-derived ONP spheroids with a nanofibrillar cellulose hydrogel and a sustained-release brainderivative neurotrophic factor delivery system. Our results demonstrated that the transplanted hESC-derived ONP spheroids survived and neuronally differentiated into otic neuronal lineages in vitro and in vivo and also extended neurites toward the bony wall of the cochlea 90 days after the transplantation without the use of immunosuppressant medication. Our data in vitro and in vivo presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear. Using our protocol to create an artificial stem cell niche in the inner ear, it is now possible to work on integrating transplanted hESC-derived ONPs further and also to work toward achieving functional auditory neurons generated from hESCs. Our findings suggest that the provision of an artificial stem cell niche can be a future approach to stem cell-replacement therapy for inner-ear regeneration.Statement of SignificanceInner ear regeneration utilizing human embryonic stem cell-derived otic neuronal progenitors (hESC-derived ONPs) has remarkable potential for treating sensorineural hearing loss. However, the local environment of the inner ear requires a suitable stem cell niche to allow hESC-derived ONP engraftment as well as neuronal differentiation. To overcome this obstacle, we utilized three-dimensional spheroid formation (direct contact), nanofibrillar cellulose hydrogel (extracellular matrix), and a neurotrophic factor delivery system to artificially create a stem cell niche in vitro and in vivo. Our in vitro and in vivo data presented here provide sufficient evidence that we have established a robust, reproducible protocol for in vivo transplantation of hESC-derived ONPs to the inner ear. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.}, keywords = {hydrogel; Stem Cell Niche; Human embryonic stem cells; Human pluripotent stem cells; Spiral ganglion neurons; The inner ear; Stem cell-replacement therapy}, year = {2020}, eissn = {1878-7568}, pages = {111-127} } @article{MTMT:31685837, title = {Origin of the Induced Pluripotent Stem Cells Affects Their Differentiation into Dopaminergic Neurons}, url = {https://m2.mtmt.hu/api/publication/31685837}, author = {Chlebanowska, Paula and Sulkowski, Maciej and Skrzypek, Klaudia and Tejchman, Anna and Muszynska, Agata and Noroozi, Rezvan and Majka, Marcin}, doi = {10.3390/ijms21165705}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {21}, unique-id = {31685837}, issn = {1661-6596}, abstract = {Neuronal differentiation of human induced pluripotent stem (iPS) cells, both in 2D models and 3D systems in vitro, allows for the study of disease pathomechanisms and the development of novel therapies. To verify if the origin of donor cells used for reprogramming to iPS cells can influence the differentiation abilities of iPS cells, peripheral blood mononuclear cells (PBMC) and keratinocytes were reprogrammed to iPS cells using the Sendai viral vector and were subsequently checked for pluripotency markers and the ability to form teratomas in vivo. Then, iPS cells were differentiated into dopaminergic neurons in 2D and 3D cultures. Both PBMC and keratinocyte-derived iPS cells were similarly reprogrammed to iPS cells, but they displayed differences in gene expression profiles and in teratoma compositions in vivo. During 3D organoid formation, the origin of iPS cells affected the levels of FOXA2 and LMX1A only in the first stages of neural differentiation, whereas in the 2D model, differences were detected at the levels of both early and late neural markers FOXA2, LMX1A, NURR1, TUBB and TH. To conclude, the origin of iPS cells may significantly affect iPS differentiation abilities in teratomas, as well as exerting effects on 2D differentiation into dopaminergic neurons and the early stages of 3D midbrain organoid formation.}, keywords = {DIFFERENTIATION; Dopaminergic neurons; origin of iPS cells; teratoma formation; midbrain organoids}, year = {2020}, eissn = {1422-0067}, orcid-numbers = {Chlebanowska, Paula/0000-0002-0486-192X; Skrzypek, Klaudia/0000-0002-3997-924X; Noroozi, Rezvan/0000-0003-2294-171X} } @article{MTMT:31685844, title = {Going Back and Forth: Episomal Vector Reprogramming of Peripheral Blood Mononuclear Cells to Induced Pluripotent Stem Cells and Subsequent Differentiation into Cardiomyocytes and Neuron-Astrocyte Co-cultures}, url = {https://m2.mtmt.hu/api/publication/31685844}, author = {de Leeuw, Victoria C. and van Oostrom, Conny T. M. and Imholz, Sandra and Piersma, Aldert H. and Hessel, Ellen V. S. and Dolle, Martijn E. T.}, doi = {10.1089/cell.2020.0040}, journal-iso = {CELL REPROGRAM}, journal = {CELLULAR REPROGRAMMING}, volume = {22}, unique-id = {31685844}, issn = {2152-4971}, abstract = {Human induced pluripotent stem cells (iPSCs) can capture the diversity in the general human population as well as provide deeper insight in cellular mechanisms. This makes them suitable to study both fundamental and applied research subjects, such as disease modeling, gene-environment interactions, personalized medicine, and chemical toxicity. In an independent laboratory, we were able to generate iPSCs originating from human peripheral blood mononuclear cells according to a modified version of a temporal episomal vector (EV)-based induction method. The iPSCs could subsequently be differentiated into two different lineages: mesoderm-derived cardiomyocytes and ectoderm-derived neuron-astrocyte co-cultures. It was shown that the neuron-astrocyte culture developed a mature phenotype within the course of five weeks and depending on the medium composition, network formation and neuron-astrocyte cell ratios could be modified. Although previously it has been described that iPSCs generated with this EV-based induction protocol could differentiate to mesenchymal stem cells, hepatocytes, cardiomyocytes, and basic neuronal cultures, we now demonstrate differentiation into a culture containing both neurons and astrocytes.}, keywords = {In Vitro; NEURONAL DIFFERENTIATION; peripheral blood mononuclear cells; human induced pluripotent stem cells; CARDIAC DIFFERENTIATION; episomal vectors}, year = {2020}, eissn = {2152-4998}, pages = {300-310} } @article{MTMT:31882109, title = {An efficient neuron-astrocyte differentiation protocol from human embryonic stem cell-derived neural progenitors to assess chemical-induced developmental neurotoxicity}, url = {https://m2.mtmt.hu/api/publication/31882109}, author = {de, Leeuw Victoria C. and van, Oostrom T. M. and Westerink, Remco H. S. and Piersma, Aldert H. and Heusinkveld, Harm J. and Hessel, Ellen V. S.}, doi = {10.1016/j.reprotox.2020.09.003}, journal-iso = {REPROD TOXICOL}, journal = {REPRODUCTIVE TOXICOLOGY}, volume = {98}, unique-id = {31882109}, issn = {0890-6238}, abstract = {Human embryonic stem cell neuronal differentiation models provide promising in vitro tools for the prediction of developmental neurotoxicity of chemicals. Such models mimic essential elements of human relevant neuronal development, including the differentiation of a variety of brain cell types and their neuronal network formation as evidenced by specific gene and protein biomarkers. However, the reproducibility and lengthy culture duration of cell models present drawbacks and delay regulatory implementation. Here we present a relatively short and robust protocol to differentiate H9-derived neural progenitor cells (NPCs) into a neuron-astrocyte co-culture. When frozen-stored NPCs were re-cultured and induced into neuron-astrocyte differentiation, they showed gene and protein expression typical for these cells, and most notably they exhibited spontaneous electrical activity within three days of culture as measured by a multi-well micro-electrode array. Modulating the ratio of astrocytes and neurons through different growth factors including glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) did not compromise the ability to develop spontaneous electrical activity. This robust neuronal differentiation model may serve as a functional component of a testing strategy for unravelling mechanisms of developmental neurotoxicity.}, year = {2020}, eissn = {1873-1708}, pages = {107-116}, orcid-numbers = {de, Leeuw Victoria C./0000-0002-3239-2227} } @article{MTMT:31685843, title = {Neural Stem Cells and Methods for Their Generation From Induced Pluripotent Stem Cellsin vitro}, url = {https://m2.mtmt.hu/api/publication/31685843}, author = {Galiakberova, Adelya A. and Dashinimaev, Erdem B.}, doi = {10.3389/fcell.2020.00815}, journal-iso = {FRONT CELL DEV BIOL}, journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, volume = {8}, unique-id = {31685843}, issn = {2296-634X}, abstract = {Neural stem cells (NSCs) provide promising approaches for investigating embryonic neurogenesis, modeling of the pathogenesis of diseases of the central nervous system, and for designing drug-screening systems. Such cells also have an application in regenerative medicine. The most convenient and acceptable source of NSCs is pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells). However, there are many different protocols for the induction and differentiation of NSCs, and these result in a wide range of neural cell types. This review is intended to summarize the knowledge accumulated, to date, by workers in this field. It should be particularly useful for researchers who are beginning investigations in this area of cell biology.}, keywords = {NEUROGENESIS; Regenerative Medicine; Pluripotent Stem Cells; IPSC; NSC; Neural Stem Cells; ESC}, year = {2020}, eissn = {2296-634X} } @article{MTMT:31467829, title = {Inducing human induced pluripotent stem cell differentiation through embryoid bodies: A practical and stable approach}, url = {https://m2.mtmt.hu/api/publication/31467829}, author = {Guo, Ning-Ning and Liu, Li-Ping and Zheng, Yun-Wen and Li, Yu-Mei}, doi = {10.4252/wjsc.v12.i1.25}, journal-iso = {WORLD J STEM CELLS}, journal = {WORLD JOURNAL OF STEM CELLS}, volume = {12}, unique-id = {31467829}, issn = {1948-0210}, abstract = {Human induced pluripotent stem cells (hiPSCs) are invaluable resources for producing high-quality differentiated cells in unlimited quantities for both basic research and clinical use. They are particularly useful for studying human disease mechanisms in vitro by making it possible to circumvent the ethical issues of human embryonic stem cell research. However, significant limitations exist when using conventional flat culturing methods especially concerning cell expansion, differentiation efficiency, stability maintenance and multicellular 3D structure establishment, differentiation prediction. Embryoid bodies (EBs), the multicellular aggregates spontaneously generated from iPSCs in the suspension system, might help to address these issues. Due to the unique microenvironment and cell communication in EB structure that a 2D culture system cannot achieve, EBs have been widely applied in hiPSC-derived differentiation and show significant advantages especially in scaling up culturing, differentiation efficiency enhancement, ex vivo simulation, and organoid establishment. EBs can potentially also be used in early prediction of iPSC differentiation capability. To improve the stability and feasibility of EB-mediated differentiation and generate high quality EBs, critical factors including iPSC pluripotency maintenance, generation of uniform morphology using micro-pattern 3D culture systems, proper cellular density inoculation, and EB size control are discussed on the basis of both published data and our own laboratory experiences. Collectively, the production of a large quantity of homogeneous EBs with high quality is important for the stability and feasibility of many PSCs related studies.}, keywords = {HETEROGENEITY; quality control; Induced pluripotent stem cells; Embryoid body; Scaling-up; three-dimensional culture; Suspension culture; early prediction; Committed differentiation}, year = {2020}, eissn = {1948-0210}, pages = {25-34} } @mastersthesis{MTMT:32468426, title = {Understanding Dishevelled-Mediated Wnt Signaling in Regulating Early Development and Stem Cell Differentiation}, url = {https://m2.mtmt.hu/api/publication/32468426}, author = {JUSTINE, MARIE NGO}, unique-id = {32468426}, year = {2020} } @article{MTMT:31685839, title = {Comparative Transcriptomic Analysis of Cerebral Organoids and Cortical Neuron Cultures Derived from Human Induced Pluripotent Stem Cells}, url = {https://m2.mtmt.hu/api/publication/31685839}, author = {Kathuria, Annie and Lopez-Lengowski, Kara and Watmuff, Bradley and Karmacharya, Rakesh}, doi = {10.1089/scd.2020.0069}, journal-iso = {STEM CELLS DEV}, journal = {STEM CELLS AND DEVELOPMENT}, volume = {29}, unique-id = {31685839}, issn = {1547-3287}, abstract = {Human induced pluripotent stem cells (iPSCs) can be differentiated along various neuronal lineages to generate two-dimensional neuronal cultures as well as three-dimensional brain organoids. Such iPSC-derived cellular models are being utilized to study the basic biology of human neuronal function and to interrogate the molecular underpinnings of disease biology. The different cellular models generated from iPSCs have varying properties in terms of the diversity and organization of the cells as well as the cellular functions that are present. To understand transcriptomic differences in iPSC-derived monolayer neuronal cultures and three-dimensional brain organoids, we differentiated eight human iPSC lines from healthy control subjects to generate cerebral organoids and cortical neuron monolayer cultures from the same set of iPSC lines. We undertook RNA-seq experiments in these model systems and analyzed the gene expression data to identify genes that are differentially expressed in cerebral organoids and two-dimensional cortical neuron cultures. In cerebral organoids, gene ontology analysis showed enrichment of genes involved in tissue development, response to stimuli, and the interferon-gamma pathway, while two-dimensional cortical neuron cultures showed enrichment of genes involved in nervous system development and neurogenesis. We also undertook comparative analysis of these gene expression profiles with transcriptomic data from the human fetal prefrontal cortex (PFC). This analysis showed greater overlap of the fetal PFC transcriptome with cerebral organoid gene expression profiles compared to monolayer cortical neuron culture profiles. Our studies delineate the transcriptomic differences between cortical neuron monolayer cultures and three-dimensional cerebral organoids and can help inform the appropriate use of these model systems to address specific scientific questions.}, keywords = {transcriptomics; CORTICAL NEURON; cerebral organoid}, year = {2020}, eissn = {1557-8534}, pages = {1370-1381} } @article{MTMT:31307709, title = {Human Induced Pluripotent Stem Cell-Derived 3D-Neurospheres are Suitable for Neurotoxicity Screening}, url = {https://m2.mtmt.hu/api/publication/31307709}, author = {Kobolák, Julianna and Teglasi, Annamaria and Bellák, Tamás and Janstova, Zofia and Molnár, Kinga and Zana, Melinda and Bock, Istvan and László, Lajos and Dinnyés, András}, doi = {10.3390/cells9051122}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {9}, unique-id = {31307709}, abstract = {We present a hiPSC-based 3D in vitro system suitable to test neurotoxicity (NT). Human iPSCs-derived 3D neurospheres grown in 96-well plate format were characterized timewise for 6-weeks. Changes in complexity and homogeneity were followed by immunocytochemistry and transmission electron microscopy. Transcriptional activity of major developmental, structural, and cell-type-specific markers was investigated at weekly intervals to present the differentiation of neurons, astrocytes, and oligodendrocytes. Neurospheres were exposed to different well-known toxicants with or without neurotoxic effect (e.g., paraquat, acrylamide, or ibuprofen) and examined at various stages of the differentiation with an ATP-based cell viability assay optimized for 3D-tissues. Concentration responses were investigated after acute (72 h) exposure. Moreover, the compound-specific effect of rotenone was investigated by a panel of ER-stress assay, TUNEL assay, immunocytochemistry, electron microscopy, and in 3D-spheroid based neurite outgrowth assay. The acute exposure to different classes of toxicants revealed distinct susceptibility profiles in a differentiation stage-dependent manner, indicating that hiPSC-based 3D in vitro neurosphere models could be used effectively to evaluate NT, and can be developed further to detect developmental neurotoxicity (DNT) and thus replace or complement the use of animal models in various basic research and pharmaceutical applications.}, keywords = {Neurotoxicity; NEURITE OUTGROWTH; Induced pluripotent stem cells; 3D culture; neurospheres}, year = {2020}, eissn = {2073-4409}, orcid-numbers = {Kobolák, Julianna/0000-0002-0986-9517; Molnár, Kinga/0000-0002-7196-5331; László, Lajos/0000-0002-2114-9109} } @article{MTMT:31031658, title = {Modeling genetic epilepsies in a dish}, url = {https://m2.mtmt.hu/api/publication/31031658}, author = {Niu, W. and Parent, J.M.}, doi = {10.1002/dvdy.79}, journal-iso = {DEV DYNAM}, journal = {DEVELOPMENTAL DYNAMICS}, volume = {249}, unique-id = {31031658}, issn = {1058-8388}, year = {2020}, eissn = {1097-0177}, pages = {56-75} } @article{MTMT:30712136, title = {Neural Progenitor Cell Derivation Methodologies for Drug Discovery Applications}, url = {https://m2.mtmt.hu/api/publication/30712136}, author = {Porterfield, Veronica}, doi = {10.1089/adt.2019.921}, journal-iso = {ASSAY DRUG DEV TECHN}, journal = {ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES}, volume = {18}, unique-id = {30712136}, issn = {1540-658X}, abstract = {Inducible pluripotent stem cells (iPSCs) are being used to model brain disorders across the continuum of neurodevelopment, neurodegenerative, and neuropsychiatric disease allowing for the mechanistic unraveling of the neurological disease state. Subsequently, there is a diverse array of cell model systems that can be used for target validation, pharmacodynamic endpoint development, and high-throughput/content assay development and screening. However, to successfully model neurological disorders with iPSCs, the disease-relevant neuron must be first identified, and it is critical to have the appropriate neuronal progenitor cell derivation and neuron differentiation protocols available to produce desired neuronal phenotypes. Moreover, special considerations are necessary if adaptation to high-throughput/content assay systems is anticipated. Discussed here are the three-dimensional embryoid body-neural rosette and two-dimensional monolayer methodologies to derive iPS neural progenitor cells and neurons with a specific focus on cortical neurons. Outlined are some of the commonalities, advantages, and disadvantages associated with both methodologies.}, year = {2020}, eissn = {1557-8127}, pages = {89-95} } @article{MTMT:31467831, title = {3D Bioprinting Pluripotent Stem Cell Derived Neural Tissues Using a Novel Fibrin Bioink Containing Drug Releasing Microspheres}, url = {https://m2.mtmt.hu/api/publication/31467831}, author = {Sharma, Ruchi and Smits, Imke P. M. and De La Vega, Laura and Lee, Christopher and Willerth, Stephanie M.}, doi = {10.3389/fbioe.2020.00057}, journal-iso = {FRONT BIOENG BIOTECHNOL}, journal = {FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY}, volume = {8}, unique-id = {31467831}, issn = {2296-4185}, abstract = {3D bioprinting combines cells with a supportive bioink to fabricate multiscale, multi-cellular structures that imitate native tissues. Here, we demonstrate how our novel fibrin-based bioink formulation combined with drug releasing microspheres can serve as a tool for bioprinting tissues using human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs). Microspheres, small spherical particles that generate controlled drug release, promote hiPSC differentiation into dopaminergic neurons when used to deliver small molecules like guggulsterone. We used the microfluidics based RX1 bioprinter to generate domes with a 1 cm diameter consisting of our novel fibrin-based bioink containing guggulsterone microspheres and hiPSC-derived NPCs. The resulting tissues exhibited over 90% cellular viability 1 day post printing that then increased to 95% 7 days post printing. The bioprinted tissues expressed the early neuronal marker, TUJ1 and the early midbrain marker, Forkhead Box A2 (FOXA2) after 15 days of culture. These bioprinted neural tissues expressed TUJ1 (15 +/- 1.3%), the dopamine marker, tyrosine hydroxylase (TH) (8 +/- 1%) and other glial markers such as glial fibrillary acidic protein (GFAP) (15 +/- 4%) and oligodendrocyte progenitor marker (O4) (4 +/- 1%) after 30 days. Also, quantitative polymerase chain reaction (qPCR) analysis showed these bioprinted tissues expressed TUJ1, NURR1 (gene expressed in midbrain dopaminergic neurons), LMX1B, TH, and PAX6 after 30 days. In conclusion, we have demonstrated that using a microsphere-laden bioink to bioprint hiPSC-derived NPCs can promote the differentiation of neural tissue.}, keywords = {Drug delivery; Tissue Engineering; Small molecules; Regenerative Medicine; guggulsterone; stems cells}, year = {2020}, eissn = {2296-4185} } @article{MTMT:30782994, title = {Pluripotent Stem Cells for Brain Repair: Protocols and Preclinical Applications in Cortical and Hippocampal Pathologies}, url = {https://m2.mtmt.hu/api/publication/30782994}, author = {Alia, Claudia and Terrigno, Marco and Busti, Irene and Cremisi, Federico and Caleo, Matteo}, doi = {10.3389/fnins.2019.00684}, journal-iso = {FRONT NEUROSCI-SWITZ}, journal = {FRONTIERS IN NEUROSCIENCE}, volume = {13}, unique-id = {30782994}, issn = {1662-4548}, abstract = {Brain injuries causing chronic sensory or motor deficit, such as stroke, are among the leading causes of disability worldwide, according to the World Health Organization; furthermore, they carry heavy social and economic burdens due to decreased quality of life and need of assistance. Given the limited effectiveness of rehabilitation, novel therapeutic strategies are required to enhance functional recovery. Since cell-based approaches have emerged as an intriguing and promising strategy to promote brain repair, many efforts have been made to study the functional integration of neurons derived from pluripotent stem cells (PSCs), or fetal neurons, after grafting into the damaged host tissue. PSCs hold great promises for their clinical applications, such as cellular replacement of damaged neural tissues with autologous neurons. They also offer the possibility to create in vitro models to assess the efficacy of drugs and therapies. Notwithstanding these potential applications, PSC-derived transplanted neurons have to match the precise sub-type, positional and functional identity of the lesioned neural tissue. Thus, the requirement of highly specific and efficient differentiation protocols of PSCs in neurons with appropriate neural identity constitutes the main challenge limiting the clinical use of stem cells in the near future. In this Review, we discuss the recent advances in the derivation of telencephalic (cortical and hippocampal) neurons from PSCs, assessing specificity and efficiency of the differentiation protocols, with particular emphasis on the genetic and molecular characterization of PSC-derived neurons. Second, we address the remaining challenges for cellular replacement therapies in cortical brain injuries, focusing on electrophysiological properties, functional integration and therapeutic effects of the transplanted neurons.}, keywords = {CORTEX; hippocampus; Brain Injuries; stroke; cell-based therapy; brain repair; pluripotent stern cells; differentiation protocols}, year = {2019}, eissn = {1662-453X} } @article{MTMT:30997152, title = {Layer-By-Layer: The Case for 3D Bioprinting Neurons to Create Patient-Specific Epilepsy Models}, url = {https://m2.mtmt.hu/api/publication/30997152}, author = {Antill-O'Brien, Natasha and Bourke, Justin and O'Connell, Cathal D.}, doi = {10.3390/ma12193218}, journal-iso = {MATERIALS}, journal = {MATERIALS}, volume = {12}, unique-id = {30997152}, abstract = {The ability to create three-dimensional (3D) models of brain tissue from patient-derived cells, would open new possibilities in studying the neuropathology of disorders such as epilepsy and schizophrenia. While organoid culture has provided impressive examples of patient-specific models, the generation of organised 3D structures remains a challenge. 3D bioprinting is a rapidly developing technology where living cells, encapsulated in suitable bioink matrices, are printed to form 3D structures. 3D bioprinting may provide the capability to organise neuronal populations in 3D, through layer-by-layer deposition, and thereby recapitulate the complexity of neural tissue. However, printing neuron cells raises particular challenges since the biomaterial environment must be of appropriate softness to allow for the neurite extension, properties which are anathema to building self-supporting 3D structures. Here, we review the topic of 3D bioprinting of neurons, including critical discussions of hardware and bio-ink formulation requirements.}, keywords = {Brain; Organoids; Neural network; 3D printing; Bioprinting; Bioink; 3D scaffolds; three-dimensional (3D) models; patient specific disease modelling}, year = {2019}, eissn = {1996-1944} } @article{MTMT:30712137, title = {Differentiation of Human Induced Pluripotent Stem Cells (iPSCs) into an Effective Model of Forebrain Neural Progenitor Cells and Mature Neurons}, url = {https://m2.mtmt.hu/api/publication/30712137}, author = {Bell, Scott and Hettige, Nuwan C. and Silveira, Heika and Peng, Huashan and Wu, Hanrong and Jefri, Malvin and Antonyan, Lilit and Zhang, Ying and Zhang, Xin and Ernst, Carl}, doi = {10.21769/BioProtoc.3188}, journal-iso = {BIO-PROTOCOL}, journal = {BIO-PROTOCOL}, volume = {9}, unique-id = {30712137}, issn = {2331-8325}, abstract = {Induced Pluripotent Stem Cells (iPSCs) are pluripotent stem cells that can be generated from somatic cells, and provide a way to model the development of neural tissues in vitro. One particularly interesting application of iPSCs is the development of neurons analogous to those found in the human forebrain. Forebrain neurons play a central role in cognition and sensory processing, and deficits in forebrain neuronal activity contributes to a host of conditions, including epilepsy, Alzheimer's disease, and schizophrenia. Here, we present our protocol for differentiating iPSCs into forebrain neural progenitor cells (NPCs) and neurons, whereby neural rosettes are generated from stem cells without dissociation and NPCs purified from rosettes based on their adhesion, resulting in a more rapid generation of pure NPC cultures. Neural progenitor cells can be maintained as long-term cultures, or differentiated into forebrain neurons. This protocol provides a simplified and fast methodology of generating forebrain NPCs and neurons, and enables researchers to generate effective in vitro models to study forebrain disease and neurodevelopment. This protocol can also be easily adapted to generate other neural lineages.}, year = {2019} } @mastersthesis{MTMT:30859380, title = {A mikroRNS-ek patogenetikai szerepe és expressziós mintázata praeeclampsiában}, url = {https://m2.mtmt.hu/api/publication/30859380}, author = {Biró, Orsolya}, doi = {10.14753/SE.2019.2269}, unique-id = {30859380}, year = {2019}, orcid-numbers = {Biró, Orsolya/0000-0002-4300-3602} } @article{MTMT:30997153, title = {Recent Progress in the Regeneration of Spinal Cord Injuries by Induced Pluripotent Stem Cells}, url = {https://m2.mtmt.hu/api/publication/30997153}, author = {Csobonyeiova, Maria and Polak, Stefan and Zamborsky, Radoslav and Danisovic, Lubos}, doi = {10.3390/ijms20153838}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {20}, unique-id = {30997153}, issn = {1661-6596}, abstract = {Regeneration of injuries occurring in the central nervous system, particularly spinal cord injuries (SCIs), is extremely difficult. The complex pathological events following a SCI often restrict regeneration of nervous tissue at the injury site and frequently lead to irreversible loss of motor and sensory function. Neural stem/progenitor cells (NSCs/NPCs) possess neuroregenerative and neuroprotective features, and transplantation of such cells into the site of damaged tissue is a promising stem cell-based therapy for SCI. However, NSC/NPCs have mostly been induced from embryonic stem cells or fetal tissue, leading to ethical concerns. The pioneering work of Yamanaka and colleagues gave rise to the technology to induce pluripotent stem cells (iPSCs) from somatic cells, overcoming these ethical issues. The advent of iPSCs technology has meant significant progress in the therapy of neurodegenerative disease and nerve tissue damage. A number of published studies have described the successful differentiation of NSCs/NPCs from iPSCs and their subsequent engraftment into SCI animal models, followed by functional recovery of injury. The aim of this present review is to summarize various iPSC- NPCs differentiation methods, SCI modelling, and the current status of possible iPSC- NPCs- based therapy of SCI.}, keywords = {DIFFERENTIATION; regeneration; Spinal Cord Injuries; Induced pluripotent stem cells; Disease modeling}, year = {2019}, eissn = {1422-0067} } @article{MTMT:30782998, title = {The Emergence of Stem Cell-Based Brain Organoids: Trends and Challenges}, url = {https://m2.mtmt.hu/api/publication/30782998}, author = {Gopalakrishnan, Jay}, doi = {10.1002/bies.201900011}, journal-iso = {BIOESSAYS}, journal = {BIOESSAYS}, volume = {41}, unique-id = {30782998}, issn = {0265-9247}, abstract = {Recent developments in 3D cultures exploiting the self-organization ability of pluripotent stem cells have enabled the generation of powerful in vitro systems termed brain organoids. These 3D tissues recapitulate many aspects of human brain development and disorders occurring in vivo. When combined with improved differentiation methods, these in vitro systems allow the generation of more complex "assembloids," which are able to reveal cell diversities, microcircuits, and cell-cell interactions within their 3D organization. Here, the ways in which human brain organoids have contributed to demystifying the complexities of brain development and modeling of developmental disorders is reviewed and discussed. Furthermore, challenging questions that are yet to be addressed by emerging brain organoid research are discussed.}, keywords = {self-assembly; microcephaly; Induced pluripotent stem cells (iPSCs); 3D cultures; assembloids; brain organoids}, year = {2019}, eissn = {1521-1878} } @article{MTMT:30712138, title = {Cellular Spheroids of Mesenchymal Stem Cells and Their Perspectives in Future Healthcare}, url = {https://m2.mtmt.hu/api/publication/30712138}, author = {Han, Hao-Wei and Asano, Shigetaka and Hsu, Shan-hui}, doi = {10.3390/app9040627}, journal-iso = {APPL SCI-BASEL}, journal = {APPLIED SCIENCES-BASEL}, volume = {9}, unique-id = {30712138}, abstract = {Intrinsic cellular properties of several types of cells are dramatically altered as the culture condition shifts from two-dimensional (2D) to three-dimensional (3D) environment. Currently, several lines of evidence have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) in regenerative medicine. MSCs not only replenish the lost cells, they also promote the regeneration of impaired tissues by modulating the immune responses. Following the development of 3D cell culture, the enhanced therapeutic efficacy of spheroid-forming MSCs have been identified in several animal disease models by promoting differentiation or trophic factor secretion, as compared to planar-cultured MSCs. Due to the complicated and multifunctional applications in the medical field, MSCs are recently named as medicinal signaling cells. In this review, we summarize the predominant differences of cell-environment interactions for the MSC spheroids formed by chitosan-based substrates and other scaffold-free approaches. Furthermore, several important physical and chemical factors affecting cell behaviors in the cell spheroids are discussed. Currently, the understanding of MSCs spheroid interactions is continuously expanding. Overall, this article aims to review the broad advantages and perspectives of MSC spheroids in regenerative medicine and in future healthcare.}, year = {2019}, eissn = {2076-3417} } @article{MTMT:30782995, title = {Fibronectin-conjugated thermoresponsive nanobridges generate three dimensional human pluripotent stem cell cultures for differentiation towards the neural lineages}, url = {https://m2.mtmt.hu/api/publication/30782995}, author = {Harknes, Linda and Chen, Xiaoli and Jia, Zhongfan and Davies, Anthony M. and Monteiro, Michael and Gray, Peter and Pera, Martin}, doi = {10.1016/j.scr.2019.101441}, journal-iso = {STEM CELL RES}, journal = {STEM CELL RESEARCH}, volume = {38}, unique-id = {30782995}, issn = {1873-5061}, abstract = {Production of 3-dimensional neural progenitor cultures from human pluripotent stem cells offers the potential to generate large numbers of cells. We utilised our nanobridge system to generate 3D hPSC aggregates for differentiation towards the neural lineage, and investigate the ability to passage aggregates while maintaining cells at a stem/progenitor stage. Over 38 days, aggregate cultures exhibited upregulation and maintenance of neural-associated markers and demonstrated up to 10 fold increase in cell number. Aggregates undergoing neural induction in the presence or absence of nanobridges demonstrated no differences in marker expression, proliferation or viability. However, aggregates formed without nanobridges were statistically significantly fewer and smaller by passage 3. Organoids, cultured from aggregates, and treated with retinoic acid or rock inhibitor demonstrated terminal differentiation as assessed by immunohistochemistry. These data demonstrate that nanobridge 3D hPSC can differentiate to neural stem/progenitor cells, and be maintained at this stage through serial passaging and expansion.}, keywords = {Neural progenitors; 3D cell culture; hESC; thermoresponsive polymer}, year = {2019}, eissn = {1876-7753} } @article{MTMT:30670996, title = {Modeling rare pediatric neurogenetic disorders with IPSCs}, url = {https://m2.mtmt.hu/api/publication/30670996}, author = {Kim, Jaemin and Nonis, David and Gabriela Otero, Maria and Mark Pierson, Tyler}, doi = {10.3934/celltissue.2019.1.1}, journal-iso = {AIMS Cell and Tissue Engineering}, journal = {AIMS Cell and Tissue Engineering}, volume = {3}, unique-id = {30670996}, year = {2019}, eissn = {2574-0105}, pages = {1-25} } @{MTMT:31882251, title = {Machine Learning to Predict Developmental Neurotoxicity with High-Throughput Data from 2D Bio-Engineered Tissues}, url = {https://m2.mtmt.hu/api/publication/31882251}, author = {Kuusisto, Finn and Santos Costa, Vitor and Hou, Zhonggang and Thomson, James and Page, David and Stewart, Ron}, booktitle = {2019 18th IEEE International Conference On Machine Learning And Applications (ICMLA)}, doi = {10.1109/ICMLA.2019.00055}, unique-id = {31882251}, year = {2019}, pages = {293-298} } @mastersthesis{MTMT:32468456, title = {Novel Techniques for Engineering Neural Tissue Using Human Induced Pluripotent Stem Cells}, url = {https://m2.mtmt.hu/api/publication/32468456}, author = {Laura, De la Vega Reyes}, unique-id = {32468456}, year = {2019} } @article{MTMT:30997151, title = {Early Actions of Neurotransmitters During Cortex Development and Maturation of Reprogrammed Neurons}, url = {https://m2.mtmt.hu/api/publication/30997151}, author = {Ojeda, Jorge and Avila, Ariel}, doi = {10.3389/fnsyn.2019.00033}, journal-iso = {FRONT SYNAPTIC NEURO}, journal = {FRONTIERS IN SYNAPTIC NEUROSCIENCE}, volume = {11}, unique-id = {30997151}, abstract = {The development of the brain is shaped by a myriad of factors among which neurotransmitters play remarkable roles before and during the formation and maturation of synaptic circuits. Cellular processes such as neurogenesis, morphological development, synaptogenesis and maturation of synapses are temporary and spatially regulated by the local or distal influence of neurotransmitters in the developing cortex. Thus, research on this area has contributed to the understanding of fundamental mechanisms of brain development and to shed light on the etiology of various human neurodevelopmental disorders such as autism and Rett syndrome (RTT), among others. Recently, the field of neuroscience has been shaken by an explosive advance of experimental approaches linked to the use of induced pluripotent stem cells and reprogrammed neurons. This new technology has allowed researchers for the first time to model in the lab the unique events that take place during early human brain development and to explore the mechanisms that cause synaptopathies. In this context, the role of neurotransmitters during early stages of cortex development is beginning to be re-evaluated and a revision of the state of the art has become necessary in a time when new protocols are being worked out to differentiate stem cells into functional neurons. New perspectives on reconsidering the function of neurotransmitters include opportunities for methodological advances, a better understanding of the origin of mental disorders and the potential for development of new treatments.}, keywords = {GLYCINE; glutamate; CORTEX; GABA; NEUROTRANSMITTERS; NEUROGENESIS; neurodevelopmental disorder; hiPSC derived neurons}, year = {2019}, eissn = {1663-3563} } @article{MTMT:31573030, title = {Efficient One-Step Induction of Human Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) Produces MSC-Derived Neurospheres (MSC-NS) with Unique Transcriptional Profile and Enhanced Neurogenic and Angiogenic Secretomes}, url = {https://m2.mtmt.hu/api/publication/31573030}, author = {Peng, Chunyang and Li, Yajiao and Lu, Li and Zhu, Jianwen and Li, Huiyu and Hu, Jingqiong}, doi = {10.1155/2019/9208173}, journal-iso = {STEM CELLS INT}, journal = {STEM CELLS INTERNATIONAL}, volume = {2019}, unique-id = {31573030}, issn = {1687-966X}, abstract = {Cell therapy has emerged as a promising strategy for treating neurological diseases such as stroke, spinal cord injury, and various neurodegenerative diseases, but both embryonic neural stem cells and human induced Pluripotent Stem Cell- (iPSC-) derived neural stem cells have major limitations which restrict their broad use in these diseases. We want to find a one-step induction method to transdifferentiate the more easily accessible Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) into neural stem/progenitor cells suitable for cell therapy purposes. In this study, UC-MSCs were induced to form neurospheres under a serum-free suspension culture with Epidermal Growth Factor- (EGF-) and basic Fibroblast Growth Factor- (bFGF-) containing medium within 12 hours. These MSC-derived neurospheres can self-renew to form secondary neurospheres and can be readily induced to become neurons and glial cells. Real-time PCR showed significantly upregulated expression of multiple stemness and neurogenic genes after induction. RNA transcriptional profiling study showed that UC-MSC-derived neurospheres had a unique transcriptional profile of their own, with features of both UC-MSCs and neural stem cells. RayBio human growth factor cytokine array analysis showed significantly upregulated expression levels of multiple neurogenic and angiogenic growth factors, skewing toward a neural stem cell phenotype. Thus, we believe that these UC-MSC-derived neurospheres have amenable features of both MSCs and neural stem/progenitor cells and have great potential in future stem cell transplantation clinical trials targeting neurological disorders.}, year = {2019}, eissn = {1687-9678} } @article{MTMT:31882187, title = {Neural microphysiological systems for in vitro modeling of peripheral nervous system disorders}, url = {https://m2.mtmt.hu/api/publication/31882187}, author = {Pollard, Kevin J and Sharma, Anup D and Moore, Michael J}, doi = {10.2217/bem-2019-0018}, journal-iso = {Bioelectronics in Medicine}, journal = {Bioelectronics in Medicine}, volume = {2}, unique-id = {31882187}, issn = {2059-1500}, year = {2019}, eissn = {2059-1519}, pages = {101-117}, orcid-numbers = {Pollard, Kevin J/0000-0002-8503-0393} } @article{MTMT:30595646, title = {Application of Human-Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders}, url = {https://m2.mtmt.hu/api/publication/30595646}, author = {Shen, Xuting and Yeung, Hoi Ting and Lai, Kwok-On}, doi = {10.1002/dneu.22644}, journal-iso = {DEV NEUROBIOL}, journal = {DEVELOPMENTAL NEUROBIOLOGY}, volume = {79}, unique-id = {30595646}, issn = {1932-8451}, abstract = {Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human-induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC-derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl-CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease-related synaptopathy. (c) 2018 Wiley Periodicals, Inc.}, keywords = {Autism spectrum disorder (ASD); Synaptognenesis; Human-induced pluripotent stem cells (hiPSCs); schizophrenia (SCZ)}, year = {2019}, eissn = {1932-846X}, pages = {20-35} } @article{MTMT:30782996, title = {The Application of Neural Stem/ Progenitor Cells for Regenerative Therapy of Spinal Cord Injury}, url = {https://m2.mtmt.hu/api/publication/30782996}, author = {Yu, Chao and Xia, Kaishun and Gong, Zhe and Ying, Liwei and Shu, Jiawei and Zhang, Feng and Chen, Qixin and Li, Fangcai and Liang, Chengzhen}, doi = {10.2174/1574888X14666190329095638}, journal-iso = {CURR STEM CELL RES THER}, journal = {CURRENT STEM CELL RESEARCH AND THERAPY}, volume = {14}, unique-id = {30782996}, issn = {1574-888X}, abstract = {Spinal cord injury (SCI) is a devastating event, and there are still no effective therapies currently available. Neural stem cells (NSCs) have gained increasing attention as promising regenerative therapy of SCI. NSCs based therapies of various neural diseases in animal models and clinical trials have been widely investigated. In this review we aim to summarize the development and recent progress in the application of NSCs in cell transplantation therapy for SCI. After brief introduction on sequential genetic steps regulating spinal cord development in vivo, we describe current experimental approaches for neural induction of NSCs in vitro. In particular, we focus on NSCs induced from pluripotent stem cells (PSCs). Finally, we highlight recent progress on the NSCs, which show great promise in the application to regeneration therapy for SCI.}, keywords = {MACROPHAGES; PATIENT; neural stem cell; spinal cord injury; pluripotent stem cell; NEURAL INDUCTION}, year = {2019}, eissn = {2212-3946}, pages = {495-503} } @article{MTMT:3357249, title = {A mikro-RNS-ek patogenetikai szerepe és expressziós mintázata praeeclampsiában}, url = {https://m2.mtmt.hu/api/publication/3357249}, author = {Biró, Orsolya and Rigó, János}, doi = {10.1556/650.2018.31025}, journal-iso = {ORV HETIL}, journal = {ORVOSI HETILAP}, volume = {159}, unique-id = {3357249}, issn = {0030-6002}, abstract = {Preeclampsia is the leading cause of maternal and fetal morbidity and mortality that affects 3-8% of pregnancies worldwide. Its main symptoms include new onset of high blood pressure and proteinuria after 20 weeks of pregnancy. The cause of the disease is still debated. microRNAs are short, non-coding RNA molecules that play a pivotal part in the posttranscriptional regulation of eukaryotic genes. They are involved in fine-tuning of vital physiological processes such as cell cycle, proliferation, differentiation and cell death. In genomic studies, hundreds of microRNAs were detected in the placenta, which are supposed to regulate placental development and contribute to uncomplicated pregnancy. Several studies have reported changes in the expression of microRNAs in pregnancy. Abnormal microRNA expression may have a role in the development of preeclampsia as it affects the proliferation, migration, and invasion of the trophoblast cells, spiral artery remodeling, and angiogenesis. Some placental microRNAs (e.g., the C19MC microRNA cluster) are able to reach the maternal circulation through their release via exosomes from the trophoblast layer. These 'circulating' microRNA molecules can be applied as biomarkers for the detection of various placental disorders owing to their stability and specificity. Orv Hetil. 2018; 159(14): 547-556.}, year = {2018}, eissn = {1788-6120}, pages = {547-556}, orcid-numbers = {Biró, Orsolya/0000-0002-4300-3602; Rigó, János/0000-0003-2762-6516} } @mastersthesis{MTMT:32789457, title = {Micropatterned Neuroectoderm Tissue Model to Study Early Neural Development and Pathogenesis}, url = {https://m2.mtmt.hu/api/publication/32789457}, author = {Geetika, Sahni}, unique-id = {32789457}, year = {2018} } @article{MTMT:30670991, title = {Modelling neurodegenerative diseases in vitro: Recent advances in 3D iPSC technologies}, url = {https://m2.mtmt.hu/api/publication/30670991}, author = {J Siney, Elodie and Kurbatskaya, Ksenia and Chatterjee, Shreyasi and Prasannan, Preeti and Mudher, Amrit and Willaime-Morawek, Sandrine}, doi = {10.3934/celltissue.2018.1.1}, journal-iso = {AIMS Cell and Tissue Engineering}, journal = {AIMS Cell and Tissue Engineering}, volume = {2}, unique-id = {30670991}, year = {2018}, eissn = {2574-0105}, pages = {1-23} } @article{MTMT:30598458, title = {Development of trophoblast cystic structures from human induced pluripotent stem cells in limited-area cell culture}, url = {https://m2.mtmt.hu/api/publication/30598458}, author = {Li, Zhuosi and Kurosawa, Osamu and Iwata, Hiroo}, doi = {10.1016/j.bbrc.2018.09.181}, journal-iso = {BIOCHEM BIOPH RES CO}, journal = {BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, volume = {505}, unique-id = {30598458}, issn = {0006-291X}, abstract = {We developed a novel engineering technique to induce differentiation of human induced pluripotent stem cells (hiPSCs) into organoids mimicking the trophectoderm (TE). Here, hiPSCs were cultured on a limited area of 2-4 mm in diameter. After 15-20 days, spherical cysts appeared on the surface of the limited area. Secretion of human chorionic gonadotrophin (hCG) began to increase after -20 days and remained dramatically elevated over the next 20 days. Limited-area-cultured cysts exhibited expression of hCG, which was a result of epithelial differentiation. Low expression levels of pluripotent genes and high expression levels of trophoblast lineage-specific genes were detected in the cells of spherical cysts. Multinucleated syncytia trophoblast was observed in the reseeded cystic cells. We observed hiPSC-derived cysts that morphologically resembled trophectoderm in vivo. The limited-area cell culture induced a three-dimensional (3D) trophectoderm organoid, which has potential for use in the study of human trophoblast differentiation and placental morphogenesis. (C) 2018 Elsevier Inc. All rights reserved.}, keywords = {cyst; trophoblast; hCG; trophectoderm; hiPSC}, year = {2018}, eissn = {1090-2104}, pages = {671-676} } @article{MTMT:30598176, title = {Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies}, url = {https://m2.mtmt.hu/api/publication/30598176}, author = {Rosati, Jessica and Ferrari, Daniela and Altieri, Filomena and Tardivo, Silvia and Ricciolini, Claudia and Fusilli, Caterina and Zalfa, Cristina and Profico, Daniela C. and Pinos, Francesca and Bernardini, Laura and Torres, Barbara and Manni, Isabella and Piaggio, Giulia and Binda, Elena and Copetti, Massimiliano and Lamorte, Giuseppe and Mazza, Tommaso and Carella, Massimo and Gelati, Maurizio and Valente, Enza Maria and Simeone, Antonio and Vescovi, Angelo L.}, doi = {10.1038/s41419-018-0990-2}, journal-iso = {CELL DEATH DIS}, journal = {CELL DEATH AND DISEASE}, volume = {9}, unique-id = {30598176}, issn = {2041-4889}, abstract = {Establishing specific cell lineages from human induced pluripotent stem cells (hiPSCs) is vital for cell therapy approaches in regenerative medicine, particularly for neurodegenerative disorders. While neural precursors have been induced from hiPSCs, the establishment of hiPSC-derived human neural stem cells (hiNSCs), with characteristics that match foetal hNSCs and abide by cGMP standards, thus allowing clinical applications, has not been described. We generated hiNSCs by a virus-free technique, whose properties recapitulate those of the clinical-grade hNSCs successfully used in an Amyotrophic Lateral Sclerosis (ALS) phase I clinical trial. Ex vivo, hiNSCs critically depend on exogenous mitogens for stable self-renewal and amplification and spontaneously differentiate into astrocytes, oligodendrocytes and neurons upon their removal. In the brain of immunodeficient mice, hiNSCs engraft and differentiate into neurons and glia, without tumour formation. These findings now warrant the establishment of clinical-grade, autologous and continuous hiNSC lines for clinical trials in neurological diseases such as Huntington's, Parkinson's and Alzheimer's, among others.}, year = {2018}, eissn = {2041-4889} } @article{MTMT:30997154, title = {Highly efficient methods to obtain homogeneous dorsal neural progenitor cells from human and mouse embryonic stem cells and induced pluripotent stem cells}, url = {https://m2.mtmt.hu/api/publication/30997154}, author = {Zhang, Meixiang and Ngo, Justine and Pirozzi, Filomena and Sun, Ying-Pu and Wynshaw-Boris, Anthony}, doi = {10.1186/s13287-018-0812-6}, journal-iso = {STEM CELL RES THER}, journal = {STEM CELL RESEARCH & THERAPY}, volume = {9}, unique-id = {30997154}, issn = {1757-6512}, abstract = {Background: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been widely used to generate cellular models harboring specific disease-related genotypes. Of particular importance are ESC and iPSC applications capable of producing dorsal telencephalic neural progenitor cells (NPCs) that are representative of the cerebral cortex and overcome the challenges of maintaining a homogeneous population of cortical progenitors over several passages in vitro. While previous studies were able to derive NPCs from pluripotent cell types, the fraction of dorsal NPCs in this population is small and decreases over several passages. Here, we present three protocols that are highly efficient in differentiating mouse and human ESCs, as well as human iPSCs, into a homogeneous and stable population of dorsal NPCs. These protocols will be useful for modeling cerebral cortical neurological and neurodegenerative disorders in both mouse and human as well as for high-throughput drug screening for therapeutic development.Methods: We optimized three different strategies for generating dorsal telencephalic NPCs from mouse and human pluripotent cell types through single or double inhibition of bone morphogenetic protein (BMP) and/or SMAD pathways. Mouse and human pluripotent cells were aggregated to form embryoid bodies in suspension and were treated with dorsomorphin alone (BMP inhibition) or combined with SB431542 (double BMP/SMAD inhibition) during neural induction. Neural rosettes were then selected from plated embryoid bodies to purify the population of dorsal NPCs. We tested the expression of key dorsal NPC markers as well as nonectodermal markers to confirm the efficiency of our three methods in comparison to published and commercial protocols.Results: Single and double inhibition of BMP and/or SMAD during neural induction led to the efficient differentiation of dorsal NPCs, based on the high percentage of PAX6-positive cells and the NPC gene expression profile. There were no statistically significant differences in the variation of PAX6 and SOX1-positive NPCs between the two human pluripotent cell-derived methods; therefore, both methods are suitable for producing stable dorsal NPCs. When further differentiated into mature neurons, NPCs gave rise to a population of almost exclusively forebrain cortical neurons, confirming the dorsal fate commitment of the progenitors.Conclusions: The methods described in this study show improvements over previously published studies and are highly efficient at differentiating human and mouse pluripotent cell types into dorsal PAX6-positive NPCs and eventually into forebrain cortical neurons.}, keywords = {NEURONAL DIFFERENTIATION; Embryonic stem cells; Induced pluripotent stem cells; Dorsal neural progenitor cells}, year = {2018}, eissn = {1757-6512} }