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Published on: February 12, 2018
EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension
Xiying Mao1, Wenjie Yin2, Miao Xu3
1Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Abstract:
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.
Insights
Inhibiting EGFR improves retinal pigment epithelial cell transplantation in retinal degeneration models. This FDA-approved drug repurposing enhances graft integration and survival, restoring vision.
Area of Science:
- Ophthalmology
- Regenerative Medicine
- Cell Biology
Background:
- Retinal pigment epithelial (RPE) cell transplantation shows promise for retinal degeneration (RD).
- Chronic graft dysfunction due to poor integration and cell loss hinders clinical success.
- Identifying molecular barriers to RPE graft integration is crucial.
Purpose of the Study:
- To investigate the molecular mechanisms underlying poor RPE graft integration.
- To identify therapeutic targets for enhancing RPE cell transplantation outcomes.
- To evaluate the efficacy of EGFR inhibition in preclinical RD models.
Main Methods:
- Single-cell transcriptomic comparison of grafted and host RPE cells.
- Multimodal imaging and spatial transcriptomics.
- Pharmacological inhibition of EGFR in fetal RPE cell suspension transplantation.
Main Results:
- EGFR expression in donor fetal RPE cells impedes functional integration.
- EGFR inhibition (EGFRi) promotes effective engraftment and restores the outer blood-retinal barrier.
- EGFRi activates CHI3L1-IL13RA2 signaling for graft reepithelialization and promotes immunosuppression.
- EGFRi extends graft survival and restrains neurodegeneration in RD models.
Conclusions:
- EGFR inhibition is a viable strategy to improve fetal RPE cell suspension transplantation.
- Repurposing FDA-approved EGFR inhibitors offers a safe and cost-effective clinical approach.
- EGFRi enhances graft integration, function, and survival, advancing RD treatment possibilities.
