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Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous systems limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortiums efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

While cell transplantation therapies show great promise as treatments for retinal degeneration, the challenge of low cell survival upon transplantation motivates exploration of materials that may serve as cell delivery vehicles and promote survival and differentiation. In this study, we explored the native matrix that surrounds the outer segments of photoreceptors and promotes their homeostasis, interphotoreceptor matrix (IPM), as a substrate for human retinal progenitor cells (hRPCs). Bovine IPM was characterized to determine its structure and biochemical composition, and processed to develop substrates for cells. Cell viability, morphology, proliferation and expression of photoreceptors marker genes were studied on IPM-based substrates in vitro. We explored different preparations of IPM as a scaffold. Lectin staining revealed that a distinct honeycomb structure of native IPM is lost during centrifugation to prepare a more concentrated suspension of matrix. Biochemical analysis of bovine IPM indicated presence of glycosaminoglycans and proteins. IPM mediated hRPC attachment and spreading with no signs of cytotoxicity. Cells proliferated more on native IPM substrates compared to IPM that was centrifuged to create a concentrated suspension. Cells cultured on IPM substrates expressed markers of photoreceptors: rhodopsin, NRL and ROM1. Together this data supports further exploration of IPM as a tool for retinal tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 891-899, 2018. [ABSTRACT FROM AUTHOR]

Many advances have been made in an attempt to treat retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa. The irreversible loss of photoreceptors is common to both, and currently no restorative clinical treatment exists. It has been shown that retinal progenitor and photoreceptor precursor cell transplantation can rescue the retinal structure and function. Importantly, retinal progenitor cells can be collected from the developing neural retina with further expansion and additional modification in vitro, and the delivery into the degenerative host can be performed as a single-cell suspension injection or as a complex graft transplantation. Previously, we have described several polymer scaffolds for culture and transplantation of retinal progenitor cells of both mouse and human origin. This tissue engineering strategy increases donor cell survival and integration. We have also shown that biodegradable poly(ɛ-caprolactone) induces mature photoreceptor differentiation from human retinal progenitor cells. However, poor adhesive properties limit its use, and therefore it requires additional surface modification. The aim of this work was to study vitronectin-mimicking oligopeptides (Synthemax II-SC) poly(ɛ-caprolactone) films and their effects on human retinal progenitor cell adhesion, proliferation, and differentiation. Here, we show that the incorporation of vitronectin-mimicking oligopeptide into poly(ɛ-caprolactone) leads to dose-dependent increases in cell adhesion; the optimum dose identified as 30 µg/ml. Inhibition of human retinal progenitor cells proliferation was seen on poly(ɛ-caprolactone) and was maintained with the hybrid scaffold. This has been shown to be beneficial for driving cell differentiation. Additionally, we observed equal expression of Nrl, rhodopsin, recoverin, and rod outer membrane 1 after differentiation on the hybrid scaffold as compared to the standard fibronectin coating of poly(ɛ-caprolactone). After transplantation into rd1 retina degenerative mice, human retinal progenitor cells were able to migrate to the outer nuclear layer and survive for three weeks. We conclude that Synthemax II-SC can be incorporated into poly(ɛ-caprolactone) to create a hybrid chemically defined scaffold for clinical application. [ABSTRACT FROM AUTHOR]