RPE-derived extracellular matrix improves graft retention and photoreceptor preservation in preclinical models of retinal degeneration

INTRODUCTION: Human pluripotent stem cells-derived retinal pigment epithelium (hPSC-RPE) represent a promising therapeutic approach for macular degeneration. This study examines whether RPE-derived extracellular matrix (RPE-ECM), enhances survival and functional outcomes following hPSC-RPE suspension transplantation in a preclinical model of retinal degeneration. METHODS: hPSC-RPE cells were cultured under three conditions: control, RPE-conditioned medium (RPE-CM), and RPE-ECM. In vitro, the cells were assessed for proliferation, monolayer organization, and gene expression. In vivo, GFP-labeled hPSC-RPE cells were co-transplanted with the corresponding treatments into the subretinal space of a mouse model of retinal degeneration. For functional assessment, the cells were injected into RCS rats, with visual acuity tracked over six months using optomotor response testing. Retinal morphometry was analyzed by immunohistology techniques to evaluate graft integration and structural rescue. RESULTS: In vitro, culture of hPSC-RPE cells with RPE-ECM enhanced proliferation and promoted monolayer formation, and increased Nidogen expression. In vivo, co-transplantation with RPE-ECM significantly improved mice retinal graft integration (47.1% vs. 3.6% in control, P < 0.001) and visual acuity over four months in RCS rats. RPE-derived ECM improved graft retention and photoreceptor preservation observed at 180 days (P < 0.001), with neuroprotective effects extending beyond the graft site to the contralateral retina. CONCLUSION: These findings suggest that co-transplantation with RPE-ECM enhances the integration and function performance of hPSC-RPE cells and may represent a promising strategy to improve graft viability within the host retina. Nevertheless, this study has several limitations, including short-term assessment in animal models and the lack of detailed ECM compositional analysis. Further studies are required to elucidate the underlying mechanisms and to evaluate the long-term transplantation potential of this approach in clinical settings.