EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension transplantation.

Numerous clinical trials have highlighted the translational potential of retinal pigment epithelial (RPE) cell transplantation in retinal degeneration (RD). However, an unsolved challenge remains in addressing chronic graft dysfunction, primarily due to poor integration and cell loss. Here, we perform a single-cell transcriptomic comparison between grafted RPE cells and host RPE. Our analysis identifies EGFR expression in donor fetal RPE cells as a significant obstacle to functional integration. Through multimodal imaging and spatial transcriptomics, we demonstrate that EGFR inhibition (EGFRi) facilitates effective engraftment of fetal RPE cell suspension, leading to the functional restoration of the outer blood-retinal barrier, and restrains neurodegeneration in preclinical RD models. This effect is mechanistically linked to graft reepithelialization via the activation of intrinsic CHI3L1-IL13RA2 signaling in EGFRi-treated donor cells. Moreover, EGFRi-induced CHI3L1 secretion contributes to immunosuppression that complements anti-lymphocytic therapy, thereby extending graft survival. Thus, repurposing Food and Drug Administration (FDA)-approved EGFR inhibitor offers a safe and cost-effective approach to advancing fetal RPE suspension transplantation into clinical practice.