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Deciphering the Molecular Signature of Human Hyalocytes in Relation to Other Innate Immune Cell Populations

ABSTRACT: Purpose: The present study compares the transcriptional profiles of human hyalo-cytes, retinal microglia as well as classical, intermediate and non-classical mono-cytes in a pairwise analysis. Methods: Using fluorescence-activated cell sorting, hyalocytes and retinal microglia were isolated from the vitreous or retinal tissue of enucleated eyes due to melano-ma of the iris, ciliary body or choroid. In addition, classical, intermediate and non-classical monocytes were isolated from whole blood. RNA sequencing was per-formed and the transcriptional profiles of all five immune cell populations were ana-lyzed using bioinformatic analysis. Results: Pairwise analysis indicated distinct differences between hyalocytes and all three subsets of monocytes, whereas a high degree of similarity was apparent when compared to retinal microglia, with comparable expression levels of established MG markers such asTREM2, P2RY12 and TMEM119. Cluster analysis based on signa-ture genes of yolk sac-derived cells as well as hematopoietic stem and progenitor cells indicated that in contrast to monocytes, human hyalocytes and retinal microglia share a common origin in the yolk sac. Among the top expressed genes in hyalo-cytes, SPP1, CD74 and C3 were significantly upregulated when compared to mon-ocytes. Despite the high level of similarity, genes such as TNF, CCL3 and CXCL8 were significantly upregulated in hyalocytes when compared to retinal microglia. In addition, ten hyalocyte-specific genes were identified, among them FOS, DUSP1 and EGR2. Conclusions: This study provides detailed insights into the molecular profile of iso-lated human hyalocytes and, for the first time, human retinal microglia. The expres-sion profile of hyalocytes is similar to that of retinal microglia and indicates that hy-alocytes are, contrary to the prevailing notion, yolk sac-derived cells. The hyalocyte-specific markers identified in this study will contribute in the future to deciphering the different roles of this fascinating cell population in health and diseases of the vitre-oretinal interface.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180705 | GEO | 2022/03/05

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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Deciphering the Molecular Signature of Human Hyalocytes in Relation to Other Innate Immune Cell Populations

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