Abstract
Purpose :
Subretinal membrane (SRM) is fibrocellular proliferation that generally takes place in the complication of retinal detachment known as proliferative vitreoretinopathy. Currently, retinotomy and stripping is the only treatment of SRM available, resulting in high recurrence rate and retinal injury. The pharmaceutical research is severely hindered due to the elusive understanding of both cellular composition and pathogenesis of SRM.
Methods :
Single-cell RNA sequencing on surgically-dissected human SRMs was performed to resolve the cellular composition and signaling pathways involved. A spontaneous mice model of SRM was invented, which was applied for the validation of the transcriptomic findings and the therapeutic efficacy of potential targets.
Results :
LHX2+ RPE-dedifferentiated cells were identified as the predominant population on SRM, which were distinguished by the activation of EGFR. Oxidative stress-induced cAMP signaling initiated the expression of LHX2 and the activation of EGFR. Inhibition of cAMP signaling prevented the genesis of SRM, but showed minimal impact on the established SRM. However, targeting the downstream EGFR significantly attenuated the presence of either forthcoming or pre-existing SRM. Unlike the canonical effect of EGFR inhibitor which resulted from the negative regulation of cell proliferation, the therapeutic effect was found to be achieved by the phenotypic switch of LHX2+ RPE-dedifferentiated cells towards the fibrolytic RPE-like state.
Conclusions :
Targeting EGFR resulted in the complete resolution of SRM and the restoration of RPE integrity. The prophylactic and therapeutic effect of EGFR inhibitor points to a promising pharmacological strategy for the treatment of subretinal fibrosis with minimal damage.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.