Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors

• Published in: Cellular and molecular life sciences : CMLS Vol. 77; no. 24; pp. 5299 - 5320
• Main Authors: Deng, Jiacheng, Ni, Zhichao, Gu, Wenduo, Chen, Qishan, Nowak, Witold Norbert, Chen, Ting, Issa Bhaloo, Shirin, Zhang, Zhongyi, Hu, Yanhua, Zhou, Bin, Zhang, Li, Xu, Qingbo
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2020; Springer Nature B.V
• Subjects: AKT protein; Animal models; Animals; Aorta; Aorta - growth & development; Aorta - metabolism; Arteriosclerosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood vessels; c-Kit protein; Cell Biology; Cell differentiation; Cell Differentiation - genetics; Cell fate; Cell Lineage - genetics; Coronary vessels; Differentiation (biology); Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium, Vascular - growth & development; Endothelium, Vascular - metabolism; Gene expression; Gene sequencing; Glycolysis; Heterogeneity; Homeostasis; Humans; Life Sciences; Mice; Original; Original Article; Progenitor cells; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-kit - genetics; Ribonucleic acid; RNA; RNA-Seq; Single-Cell Analysis - methods; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; TOR protein; TOR Serine-Threonine Kinases - genetics; Tracing; Vascular diseases; Endothelial repair; Single-cell RNA-sequencing; Metabolism; Lineage tracing; Stem cells
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03480-4

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.