Single-cell transcriptome analyses reveal unique 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 Jr Fulton; Zheng Dong; Akrit Sodhi; Ruth B Caldwell; Yuqing Huo

doi:10.1172/jci.insight.160940

Single-cell transcriptome analyses reveal unique 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 Jr Fulton, Zheng Dong, Akrit Sodhi, Ruth B Caldwell, Yuqing Huo

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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 characterize the transcriptional profiles and metabolic pathways of pro-angiogenic microglia in a mouse model of oxygen-induced proliferative retinopathy (OIR). Using transcriptional single-cell sorting, we comprehensively map all microglia populations in retinas of room air (RA) and OIR mice. We unveil several unique types of PR-associated microglia (PRAM) and identify 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 hyper-metabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes and pro-angiogenic insulin-like growth factor 1. Immunohistochemical staining shows these PRAMs were spatially located within or around neovascular (NV) tufts. These unique microglia-types have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.

Original language	English (US)
Article number	e160940
Journal	JCI Insight
Volume	7
Issue number	23
Early online date	Oct 20 2022
DOIs	https://doi.org/10.1172/jci.insight.160940 https://doi.org/10.1172/jci.insight.160940
State	Published - Dec 8 2022

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Medicine(all)

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Liu, Z., Shi, H., Xu, J., Yang, Q., Ma, Q., Mao, X., Xu, Z., Zhou, Y., Da, Q., Cai, Y., Fulton, D. J., Dong, Z., Sodhi, A., Caldwell, R. B., & Huo, Y. (2022). Single-cell transcriptome analyses reveal unique microglia types associated with proliferative retinopathy. JCI Insight, 7(23), [e160940]. https://doi.org/10.1172/jci.insight.160940, https://doi.org/10.1172/jci.insight.160940

Liu, Z, Shi, H, Xu, J, Yang, Q, Ma, Q, Mao, X, Xu, Z, Zhou, Y, Da, Q, Cai, Y, Fulton, DJ , Dong, Z, Sodhi, A, Caldwell, RB & Huo, Y 2022, 'Single-cell transcriptome analyses reveal unique microglia types associated with proliferative retinopathy', JCI Insight, vol. 7, no. 23, e160940. https://doi.org/10.1172/jci.insight.160940, https://doi.org/10.1172/jci.insight.160940

@article{23ac1ab88c10435e8776d10617683cbb,

title = "Single-cell transcriptome analyses reveal unique 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 characterize the transcriptional profiles and metabolic pathways of pro-angiogenic microglia in a mouse model of oxygen-induced proliferative retinopathy (OIR). Using transcriptional single-cell sorting, we comprehensively map all microglia populations in retinas of room air (RA) and OIR mice. We unveil several unique types of PR-associated microglia (PRAM) and identify 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 hyper-metabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes and pro-angiogenic insulin-like growth factor 1. Immunohistochemical staining shows these PRAMs were spatially located within or around neovascular (NV) tufts. These unique microglia-types have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.",

author = "Zhiping Liu and Huidong Shi and Jiean Xu and Qiuhua Yang and Qian Ma and Xiaoxiao Mao and Zhimin Xu and Yaqi Zhou and Qingen Da and Yongfeng Cai and Fulton, {David Jr} and Zheng Dong and Akrit Sodhi and Caldwell, {Ruth B} and Yuqing Huo",

note = "Funding Information: This work is supported by National Natural Science Foundation of China grants 81870324 (ZL); NIH grants R01HL134934 (YH), R01EY030500 (RC and YH), R01EY033369-01 (RC and YH), R01EY033737-01 (YH and RC), R01EY011766 (RC), and R01CA264983-01(HS); VA Merit Review grant BX002035 (ZD); and NEI Center Core grant for vision research (P30). Publisher Copyright: {\textcopyright} 2022, Liu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2022",

month = dec,

day = "8",

doi = "10.1172/jci.insight.160940",

language = "English (US)",

volume = "7",

journal = "JCI insight",

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publisher = "The American Society for Clinical Investigation",

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TY - JOUR

T1 - Single-cell transcriptome analyses reveal unique microglia types associated with proliferative retinopathy

AU - Liu, Zhiping

AU - Shi, Huidong

AU - Xu, Jiean

AU - Yang, Qiuhua

AU - Ma, Qian

AU - Mao, Xiaoxiao

AU - Xu, Zhimin

AU - Zhou, Yaqi

AU - Da, Qingen

AU - Cai, Yongfeng

AU - Fulton, David Jr

AU - Dong, Zheng

AU - Sodhi, Akrit

AU - Caldwell, Ruth B

AU - Huo, Yuqing

N1 - Funding Information: This work is supported by National Natural Science Foundation of China grants 81870324 (ZL); NIH grants R01HL134934 (YH), R01EY030500 (RC and YH), R01EY033369-01 (RC and YH), R01EY033737-01 (YH and RC), R01EY011766 (RC), and R01CA264983-01(HS); VA Merit Review grant BX002035 (ZD); and NEI Center Core grant for vision research (P30). Publisher Copyright: © 2022, Liu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PY - 2022/12/8

Y1 - 2022/12/8

N2 - 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 characterize the transcriptional profiles and metabolic pathways of pro-angiogenic microglia in a mouse model of oxygen-induced proliferative retinopathy (OIR). Using transcriptional single-cell sorting, we comprehensively map all microglia populations in retinas of room air (RA) and OIR mice. We unveil several unique types of PR-associated microglia (PRAM) and identify 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 hyper-metabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes and pro-angiogenic insulin-like growth factor 1. Immunohistochemical staining shows these PRAMs were spatially located within or around neovascular (NV) tufts. These unique microglia-types have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.

AB - 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 characterize the transcriptional profiles and metabolic pathways of pro-angiogenic microglia in a mouse model of oxygen-induced proliferative retinopathy (OIR). Using transcriptional single-cell sorting, we comprehensively map all microglia populations in retinas of room air (RA) and OIR mice. We unveil several unique types of PR-associated microglia (PRAM) and identify 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 hyper-metabolic microglia subset that expresses high levels of activating microglia markers, glycolytic enzymes and pro-angiogenic insulin-like growth factor 1. Immunohistochemical staining shows these PRAMs were spatially located within or around neovascular (NV) tufts. These unique microglia-types have the potential to promote retinal angiogenesis, which may have important implications for future treatment of PR and other pathological ocular angiogenesis-related diseases.

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U2 - 10.1172/jci.insight.160940

DO - 10.1172/jci.insight.160940

M3 - Article

C2 - 36264636

SN - 2379-3708

VL - 7

JO - JCI insight

JF - JCI insight

IS - 23

M1 - e160940

ER -

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

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