PURPOSE. Proliferative vitreoretinopathy (PVR) remains an unresolved clinical challenge
and can lead to frequent revision surgery and blindness vision loss. The aim of this
study was to characterize the microenvironment of epiretinal PVR tissue, in order
to shed more light on the complex pathophysiology and to unravel new treatment options.METHODS.
A total of 44 tissue samples were analyzed in this study, including 19 epiretinal
PVRs, 13 epiretinal membranes (ERMs) from patients with macular pucker, as well as
12 internal limiting membranes (ILMs). The cellular and molecular microenvironment
was assessed by cell type deconvolution analysis (xCell), RNA sequencing data and
single-cell imaging mass cytometry. Candidate drugs for PVR treatment were identified
in silico via a transcriptome-based drug-repurposing approach.RESULTS. RNA sequencing
of tissue samples demonstrated distinct transcriptional profiles of PVR, ERM, and
ILM samples. Differential gene expression analysis revealed 3194 upreg-ulated genes
in PVR compared with ILM, including FN1 and SPARC, which contribute to biological
processes, such as extracellular matrix (ECM) organization. The xCell and IMC analyses
showed that PVR membranes were composed of macrophages, retinal pigment epithelium,
and alpha-SMA-positive myofibroblasts, the latter predominantly characterized by the
co-expression of immune cell signature markers. Finally, 13 drugs were identified
as potential therapeutics for PVR, including aminocaproic acid and various topoisomerase-2A
inhibitors.CONCLUSIONS. Epiretinal PVR membranes exhibit a unique and complex transcriptional
and cellular profile dominated by immune cells and myofibroblasts, as well as a variety
of ECM components. Our findings provide new insights into the pathophysiology of PVR
and suggest potential targeted therapeutic options.
