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Single-cell transcriptomic atlas reveals tissue architecture and deciphers pathological reprogramming during retinal ischemia in Macaca fascicularis

ABSTRACT: Acute retinal arterial ischemia diseases (ARAIDs) are ocular emergencies that require immediate intervention within a restricted therapeutic window to prevent blindness. Howbeit, the underlying molecular mechanisms contributing to the pathogenesis of ARAIDs remain enigmatic. Herein, this study aims to present the single cell RNA sequencing (scRNA-seq) atlas of ischemic alterations in the primate retina as a preliminary endeavor in understanding the molecular complexities of ARAIDs. In our study, it was determined that rods experienced a significant metabolic reprogramming during retina ischemia, resulting in compromised mitochondrial functions. Furthermore, we observed a noteworthy transcriptional alteration in the activation of microglia induced by ischemia. The targeted correction of the proinflammatory cytokine CXCL8 effectively suppresses microglia M1 polarization in retinal ischemia, ultimately reducing the pro-inflammatory transformation. In addition, our study has observed the apoptotic inclination of endothelial cells and the heightened interaction with microglia, which signifies the influence of microglia in disrupting the blood barrier during the initial phase. In conclusion, our research has successfully identified and described the pathological alterations occurring in several significant cell types during a short period of ischemia. These observations provide valuable insights for ameliorating retinal damage and promoting the restoration of vision.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE242229 | GEO | 2023/09/06

REPOSITORIES: GEO

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Project description:Microglia are the tissue-resident macrophages of the retina and brain, being critically involved in organ development, tissue homeostasis, and response to cellular damage. Until now, little is known about the transcriptional profile of human retinal microglia and how they differentiate from peripheral monocytes, as well as from brain microglia. Additionally, the degree to which mice are suitable models for human retinal microglia is still not clear. The present study applies fluorescence-activated cell sorting to isolate human retinal microglia from enucleated eyes and compares their transcriptional profile with that of whole retinal tissue, as well as classical, intermediate and non-classical monocytes. In addition, human retinal microglia are compared to murine retinal microglia, isolated from at least two-years old Cx3cr1GFP/+ mice, as well as human brain microglia obtained from the literature. Several overexpressed genes were identified in retinal microglia when compared to whole retinal tissue, as well as classical, intermediate, and non-classical monocytes, among them IL1B, C2, C3, TREM2, P2RY12 and SPP1. In relation to whole retina sequencing, several risk genes, such as APOE and TGBR1, as well as PLXDC2 and ARHGAP22 associated with age-related macular degeneration (AMD) and diabetic retinopathy (DRP), were preferentially expressed in retinal microglia, indicating their potential pathophysiological involvement. The top expressed genes exhibited a strong consistency between retinal and brain microglia, among them CD74, SPP1, ACTB, FTL and C3. There was a high degree of similarity between human and murine retinal microglia, although there were several species-specific genes, revealing for which genes mice are suitable models for human retinal microglia. This study provides detailed insights into the molecular profile of human retinal microglia and indicate a high similarity to brain microglia. It advances our under-standing about their role in human retinal disease, such as AMD and DRP. The similarities and differences between human and mice will facilitate the transferability of knowledge between both species.

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Single-cell transcriptomic atlas reveals tissue architecture and deciphers pathological reprogramming during retinal ischemia in Macaca fascicularis

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