Dataset Information

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.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9746914 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Zhiping Z Shi Huidong H Xu Jiean J Yang Qiuhua Q Ma Qian Q Mao Xiaoxiao X Xu Zhimin Z Zhou Yaqi Y Da Qingen Q Cai Yongfeng Y Fulton David Jr DJ Dong Zheng Z Sodhi Akrit A Caldwell Ruth B RB Huo Yuqing Y

JCI insight 20221208 23

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 profil ...[more]

PMID: 36264636

Similar Datasets

Project description:Esophageal squamous cell carcinoma (ESCC) is a tumor composed of heterogeneous cells that easily become radioresistant, which leads to tumor recurrence. The most commonly used treatment for ESCC is fractionated irradiation (FIR) therapy that utilizes ionizing radiation to directly induce cytotoxic cell death. However, this treatment may not be able to eliminate all cancer cells due to high adaptive evolution. To determine whether the transcriptome dynamics during ESCC recurrence formation are associated with FIR response, an in vitro cell culture model for ESCC radioresistance that mimics the common radiotherapy process in patients with ESCC was established in the present study. High‑throughput sequencing analysis of in vitro cultured ESCC cells was performed using different cumulative irradiation doses, as well as tumor samples from FIR‑treated patients with ESCC before and after the development of radioresistance. Radioresistance‑associated genes and signaling pathways that were aberrantly expressed in radioresistant ESCC cells were identified, including autophagy‑related 9B (regulation of autophagy), DNA damage‑inducible transcript 4, myoglobin and plasminogen activator tissue type, which are associated with response to hypoxia, Bcl2‑binding component 3, tumor protein P63 and interferon γ‑inducible protein 16, which are associated with DNA damage response. The heterogeneity and dynamic gene expression of ESCC cells during acquired radioresistance were further studied in primary (41 single cells), 12 Gy FIR‑treated (87 single cells) and 30 Gy FIR‑treated (89 single cells) cancer cells using a single‑cell RNA sequencing approach. The results of the present study comprehensively characterized the transcriptome dynamics during acquired radioresistance in an in vitro model of ESCC and patient tumor samples at the population and single cell level. Single‑cell RNA sequencing revealed the heterogeneity of irradiated ESCC cells and an increase in the radioresistant ESCC cell subpopulation during acquired radioresistance. Overall, these results are of potential clinical relevance as they identify a number of signaling molecules associated with radioresistance, as well as opportunities for the development of novel therapeutic options for the treatment of ESCC.

Project description:BackgroundProliferative diabetic retinopathy (PDR) is among the primary causes of blindness in individuals with diabetes. Elevated lactate levels have been identified as a critical biomarker associated with the prognosis of PDR. While significant lactate accumulation has been observed in the vitreous fluid of PDR patients, the detailed pathways through which lactate impacts pathological neovascularization remain insufficiently elucidated.MethodsThe study employed single-cell RNA sequencing (scRNA-seq) to identify and characterize lactate-associated cell type in PDR patients. Key gene expression profiles and molecular pathways associated with lactate metabolism were analyzed. In vitro experiments were conducted using microglial cell cultures treated with high-glucose conditions (50 mM) to assess the induction of lactate metabolism-related genes. Additionally, an oxygen-induced retinopathy (OIR) mouse model was used to evaluate the impact of abemaciclib, an FDA-approved proliferation inhibitor, on retinal neovascularization.ResultsTo the best of our knowledge, this investigation is the first to delineate a novel microglial subset, designated as MKI67+ microglia, distinguished by robust upregulation of genes implicated in lactate metabolic processes and proliferation, such as MKI67, PARK7 and LDHA, as well as a pronounced enrichment of glycolysis-associated molecular pathways. This unique cell type promotes angiogenesis by interacting with endothelial cells via secreted phosphoprotein 1 (SPP1)-Integrin alpha 4 (ITGA4) signaling. In vitro experiments have shown the use of 50 mM high glucose to simulate microglia in PDR environment and observe its promotion of vascular proliferation. In the in vivo OIR model, treatment with abemaciclib, a FDA-approved proliferation inhibitor, significantly reduced neovascularization.ConclusionThe identification of MKI67+ microglia as a cell type strongly associated with lactate metabolism provides a novel perspective on the mechanisms underlying PDR onset. These findings expand our understanding of the cellular and metabolic dynamics in PDR, emphasizing potential implications for targeted therapeutic interventions.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets