Single-cell RNA Sequencing Reveals the Role of Heat Shock Protein 90 in Müller Cells Proliferation via the Necroptosis/MAPK Pathway in Diabetes

Abstract Purpose Understanding the complex pathology of diabetic retinopathy (DR) was challenging due to the intricate cellular structure of the retina. Methods We performed single-cell RNA sequencing (scRNA-seq) on retinas from 4 diabetic patients and 2 nondiabetic patients. Bioinformatics analysis combined with experimental exploration using in vivo and in vitro DR models were performed to explore the pathogenesis of the Müller cells (MCs) in DR. Results We identified 9 major cell types and revealed that diabetes impacted the retinal cell type composition as well as specific genes expression, and altered cell-cell communication. Heat shock protein 90 (HSP90), which was downregulated in the MCs of the diabetic patients, may function as a hub gene, and the significant functional pathways were the necroptosis (RIP1/RIP3/MLKL) and mitogen-activated protein kinase(MAPK) pathways. Furthermore, our results of in vivo and in vitro DR models suggested that the downregulation of HSP90 may induce DR-associated MCs proliferation. Conclusion Our study offered new insight into the cellular and molecular mechanism underlying the pathogenesis of DR, revealing the suppressive role of HSP90 in MCs proliferation, which could be targeted to treat DR.