Recent preclinical investigations and clinical trials with stem cells mostly studied
bone-marrow-derived mononuclear cells (BM-MNCs), which so far failed to meet clinically
significant functional study endpoints. BM-MNCs containing small proportions of stem
cells provide little regenerative potential, while mesenchymal stem cells (MSCs) promise
effective therapy via paracrine impact. Genetic engineering for rationally enhancing
paracrine effects of implanted stem cells is an attractive option for further development
of therapeutic cardiac repair strategies. Non-viral, efficient transfection methods
promise improved clinical translation, longevity and a high level of gene delivery.
Hypoxia-induced factor 1 alpha is responsible for pro-angiogenic, anti-apoptotic and
anti-remodeling mechanisms. Here we aimed to apply a cellular gene therapy model in
chronic ischemic heart failure in pigs. A non-viral circular minicircle DNA vector
(MiCi) was used for in vitro transfection of porcine MSCs (pMSC) with HIF1 alpha (pMSC-MiCi-HIF-1
alpha). pMSCs-MiCi-HIF-1 alpha were injected endomyocardially into the border zone
of an anterior myocardial infarction one month post-reperfused-infarct. Cell injection
was guided via 3D-guided NOGA electro-magnetic catheter delivery system. pMSC-MiCi-HIF-1
alpha delivery improved cardiac output and reduced myocardial scar size. Abundances
of pro-angiogenic proteins were analyzed 12, 24 h and 1 month after the delivery of
the regenerative substances. In a protein array, the significantly increased angiogenesis
proteins were Activin A, Angiopoietin, Artemin, Endothelin-1, MCP-1; and remodeling
factors ADAMTS1, FGFs, TGFb1, MMPs, and Serpins. In a qPCR analysis, increased levels
of angiopeptin, CXCL12, HIF-1 alpha and miR-132 were found 24 h after cell-based gene
delivery, compared to those in untreated animals with infarction and in control animals.
Expression of angiopeptin increased already 12 h after treatment, and miR-1 expression
was reduced at that time point. In total, pMSC overexpressing HIF-1 alpha showed beneficial
effects for treatment of ischemic injury, mediated by stimulation of angiogenesis.
