The sexed retina: a combined single-cell and bulk RNA sequencing analysis of healthy aging human retina

Abstract Background The human retina is subjected to age-related neurodegenerative diseases like other CNS tissues, but little attention is paid to sex. Previous studies have exhibited divergent sexual responses to aging, but how gene expression profiles differ between males and females and how these differences could be associated with age-related retinal diseases remains elusive. As such, we performed a combined analysis of single-cell RNA (scRNA) and bulk RNA sequencing of the healthy aged retina of females and males. Results: We discovered significant differences in transcriptome profiles in the macular and peripheral retina regions between the two sexes. Despite all major retinal cell types being identified in female and male healthy aging retinas, sex specificity is prominent in gene expression and retinal disease-related genes. Cell-to-cell communication analysis revealed an elevated CCL7/TGFB1/VEGFA-associated interaction in the glial cells of the female retina. Finally, we identified MC1 as a subpopulation of microglia responsible for the susceptibility to immune inflammation in the macular retina of females. In males, the differentially expressed genes of retinal glial cells were associated with regeneration and protection. Conclusions: This study provides a comprehensive comparison between females and males and found a profound dissimilarity between sexes in healthy aging human retinas, suggesting that age-related changes in the retina are sex-related and that the female retina is more susceptible to neuroinflammation. This study provides valuable insights into identifying therapeutic and prevention targets in retinal aging diseases by considering sex as an important factor.