Single-cell transcriptome analyses reveal microglia types associated with proliferative retinopathy
Zhiping Liu, Huidong Shi, Jiean Xu, Qiuhua Yang, Qian Ma, Xiaoxiao Mao, Zhimin Xu, Yaqi Zhou, Qingen Da, Yongfeng Cai, David J.R. Fulton, Zheng Dong, Akrit Sodhi, Ruth B. Caldwell, Yuqing Huo
Zhiping Liu, Huidong Shi, Jiean Xu, Qiuhua Yang, Qian Ma, Xiaoxiao Mao, Zhimin Xu, Yaqi Zhou, Qingen Da, Yongfeng Cai, David J.R. Fulton, Zheng Dong, Akrit Sodhi, Ruth B. Caldwell, Yuqing Huo
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Research Article Angiogenesis Ophthalmology

Single-cell transcriptome analyses reveal microglia types associated with proliferative retinopathy

Abstract

Pathological angiogenesis is a major cause of irreversible blindness in individuals of all age groups with proliferative retinopathy (PR). Mononuclear phagocytes (MPs) within neovascular areas contribute to aberrant retinal angiogenesis. Due to their cellular heterogeneity, defining the roles of MP subsets in PR onset and progression has been challenging. Here, we aimed to investigate the heterogeneity of microglia associated with neovascularization and to characterize the transcriptional profiles and metabolic pathways of proangiogenic microglia in a mouse model of oxygen-induced PR (OIR). Using transcriptional single-cell sorting, we comprehensively mapped all microglia populations in retinas of room air (RA) and OIR mice. We have unveiled several unique types of PR-associated microglia (PRAM) and identified markers, signaling pathways, and regulons associated with these cells. Among these microglia subpopulations, we found a highly proliferative microglia subset with high self-renewal capacity and a hypermetabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes, and proangiogenic Igf1. IHC staining shows that these PRAM were spatially located within or around neovascular tufts. These unique types of microglia have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis–related diseases.

Authors

Zhiping Liu, Huidong Shi, Jiean Xu, Qiuhua Yang, Qian Ma, Xiaoxiao Mao, Zhimin Xu, Yaqi Zhou, Qingen Da, Yongfeng Cai, David J.R. Fulton, Zheng Dong, Akrit Sodhi, Ruth B. Caldwell, Yuqing Huo

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Figure 9

OIR and RA microglia subtypes can be identified in microglia populations from E14.5, P4, P5, and P30 mouse brain.

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OIR and RA microglia subtypes can be identified in microglia populations...
(A) UMAP plot of microglia from E14.5, P4, P5, and P30 mouse brain (22). (B) UMAP plot of OIR and RA microglia after reference mapping and label transferring. The OIR and RA microglia were used as query data, and microglia from Hammond et al. (22) were used as the reference data set. Seurat V4 reference mapping function was used. Cells are labeled by predicted cluster names in A and colored accordingly. (C) UMAP plot of OIR and RA microglia after reference mapping and label transferring. Cells are labeled by the cluster names as in Figure 1B and colored accordingly. (D) UMAP plots showing gene signature AUC scores of several mouse brain microglia subpopulations from ref. 22 in OIR and RA microglia. (E) Bar plots showing the gene expression of subpopulation-specific markers in mouse brain microglia at different ages and upon injury from ref. 22. UMI counts, which represent expression levels of corresponding genes in microglia from embryonic (E14.5), postnatal early development (P4/P5), and young (P30), adult (P100), and aged (P540) mouse brain are shown. Data for control and injury microglia isolated at day 7 from saline-injected and lysolecithin-injected mouse white matter (P100) are shown to the left of the dashed gray lines. Plots were generated from https://www.microgliasinglecell.com.