Integrated Transcriptomics and Experimental Validation Reveal Müller Cell-Driven PANoptosis in Diabetic Retinopathy...

Area of Science:

• Ophthalmology
• Cell Biology
• Genetics

Background:

• Diabetic retinopathy (DR) is a leading cause of vision loss in diabetes patients.
• PANoptosis, a pro-inflammatory programmed cell death, is implicated in DR pathogenesis.
• Understanding membrane protein-mediated PANoptosis in DR is crucial for therapeutic development.

Purpose of the Study:

• To investigate the role of PANoptosis in diabetic retinopathy progression.
• To identify key cell populations and signaling pathways involved in DR-related PANoptosis.
• To screen for potential therapeutic targets and coregulated genes.

Main Methods:

• Integrated single-cell and bulk transcriptomics to identify differentially expressed PANoptosis-related genes (DE-PRGs).
• Utilized ssGSEA for PANoptosis scoring and CellChat for intercellular communication analysis.
• Validated findings in DR rat models and high-glucose-treated retinal Müller cells (RMC-1).

Main Results:

• Identified 27 DE-PRGs linked to TNF, programmed cell death (PCD), and p53 signaling.
• Müller cells, particularly the "Müller2" subpopulation, showed elevated PANoptosis scores and mediated pro-apoptotic signals via the PSAP-GPR37 axis.
• High glucose induced cell death and PANoptosis markers in vitro; PSAP knockdown attenuated these effects.

Conclusions:

• Müller cells, specifically the Müller2 subpopulation, are central drivers of PANoptosis in diabetic retinopathy through PSAP-GPR37 signaling.
• Identified hub genes and PSAP as potential targets for cell-subpopulation-specific interventions in DR.
• This research provides a foundation for developing targeted therapies for diabetic retinopathy.