Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors
Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors
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单细胞基因谱和谱系追踪分析揭示了祖细胞修复内皮细胞的新机制
DOI：
10.1007/s00018-020-03480-4
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发表时间：
2020-03-13
影响因子：
8
通讯作者：
Xu, Qingbo
中科院分区：
文献类型：
--
作者：
Deng, Jiacheng;Ni, Zhichao;Xu, Qingbo
干细胞/祖细胞（SPCs）被认为参与血管修复。然而，SPCs在大血管内皮修复中的确切作用仍存在争议。本研究旨在描绘内源性血管SPCs在大血管中的细胞异质性以及可能的功能作用。利用单细胞RNA测序（scRNA - seq）和基因谱系追踪小鼠模型，我们揭示了SPCs的细胞异质性，即小鼠主动脉中的c - Kit（+）细胞，并发现内源性c - Kit（+）细胞在生理和病理条件下在主动脉中获得内皮细胞命运。在稳态期间，虽然c - Kit（+）细胞有助于动脉粥样硬化易患区域的主动脉内皮更新，但在移植性动脉硬化中，非骨髓来源的受体c - Kit（+）细胞会取代管腔和微血管内皮细胞。对scRNA - seq数据的单细胞拟时间分析和体外细胞实验表明，血管SPCs显示出内皮分化潜能，并在细胞分化过程中经历代谢重编程，其中AKT/mTOR依赖的糖酵解对内皮基因表达至关重要。这些发现证明了c - Kit谱系细胞在主动脉内皮更新和替换中的关键作用，并可能为血管疾病的治疗策略提供见解。
Stem/progenitor cells (SPCs) have been implicated to participate in vascular repair. However, the exact role of SPCs in endothelial repair of large vessels still remains controversial. This study aimed to delineate the cellular heterogeneity and possible functional role of endogenous vascular SPCs in large vessels. Using single-cell RNA-sequencing (scRNA-seq) and genetic lineage tracing mouse models, we uncovered the cellular heterogeneity of SPCs, i.e., c-Kit(+)cells in the mouse aorta, and found that endogenous c-Kit(+)cells acquire endothelial cell fate in the aorta under both physiological and pathological conditions. While c-Kit(+)cells contribute to aortic endothelial turnover in the atheroprone regions during homeostasis, recipient c-Kit(+)cells of nonbone marrow source replace both luminal and microvessel endothelial cells in transplant arteriosclerosis. Single-cell pseudotime analysis of scRNA-seq data and in vitro cell experiments suggest that vascular SPCs display endothelial differentiation potential and undergo metabolic reprogramming during cell differentiation, in which AKT/mTOR-dependent glycolysis is critical for endothelial gene expression. These findings demonstrate a critical role for c-Kit lineage cells in aortic endothelial turnover and replacement, and may provide insights into therapeutic strategies for vascular diseases.