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

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Abstract

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.

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Abbreviations

2-DG:

2-Deoxyglucose

ECs:

Endothelial cells

ECAR:

Extracellular acidification rate

MSC:

Mesenchymal stromal cell

NK:

Natural killer

OCR:

Oxygen consumption rate

RBC:

Red blood cells

Sca-1/Ly6a:

Stem cell antigen-1/lymphocyte antigen 6 complex, locus A

scRNA-seq:

Single-cell RNA-sequencing

SMCs:

Smooth muscle cells

SPCs:

Stem/progenitor cells

TCA cycle:

Tricarboxylic acid cycle

tdTomato/tdT:

Tandem dimer Tomato

UMAP:

Uniform manifold approximation and projection

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This work was supported by grants from British Heart Foundation (RG/14/6/31144), National Natural Science Foundation of China (81220108004, 81570249, 81930010, 81870206, 91339102, 91639302, 91539103, and 31830039), Zhejiang Provincial Natural Science Foundation (LD18H020001) and Royal Society-Newton Advanced Fellowship (NA170109). Some panels in the figure were produced using Servier Medical Art under a Creative Commons Attribution 3.0 Unported License.

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  1. Jiacheng Deng and Zhichao Ni have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Jiacheng Deng, Qishan Chen, Ting Chen, Li Zhang & Qingbo Xu

  2. School of Cardiovascular Medicine and Science, BHF Centre, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK

    Jiacheng Deng, Zhichao Ni, Wenduo Gu, Witold Norbert Nowak, Shirin Issa Bhaloo, Zhongyi Zhang, Yanhua Hu & Qingbo Xu

  3. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academic of Sciences, Shanghai, 200031, China

    Bin Zhou

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Deng, J., Ni, Z., Gu, W. et al. Single-cell gene profiling and lineage tracing analyses revealed novel mechanisms of endothelial repair by progenitors. Cell. Mol. Life Sci. 77, 5299–5320 (2020). https://doi.org/10.1007/s00018-020-03480-4

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