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Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells

View ORCID ProfileChen Zhang, View ORCID ProfileXueshuai Han, View ORCID ProfileJingkun Liu, View ORCID ProfileLei Chen, View ORCID ProfileYing Lei, View ORCID ProfileKunying Chen, View ORCID ProfileJia Si, View ORCID ProfileTian-yi Wang, View ORCID ProfileHui Zhou, View ORCID ProfileXiaoyun Zhao, View ORCID ProfileXiaohui Zhang, View ORCID ProfileYihua An, View ORCID ProfileYueying Li, View ORCID ProfileQian-fei Wang
doi: https://doi.org/10.1101/2021.11.24.469676
Chen Zhang
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
4Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China
9Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Qingdao 266035, China
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  • ORCID record for Chen Zhang
Xueshuai Han
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Jingkun Liu
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Lei Chen
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Ying Lei
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Kunying Chen
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Jia Si
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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Tian-yi Wang
5International Department, Liangxiang Campus, Beijing University of Chinese Medicine, Beijing 102401, China
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Hui Zhou
6Yihua Biotechnology Co. Ltd, Beijing 100000, China
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Xiaoyun Zhao
4Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China
9Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Qingdao 266035, China
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Xiaohui Zhang
7Peking University People’s Hospital, Peking University Institute of Hematology, Beijing 100044, China
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Yihua An
8Department of Neurosurgery, First Medical Center, General Hospital of Chinese PLA, Beijing 100853, China
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Yueying Li
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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  • For correspondence: wangqf@big.ac.cn liyy@big.ac.cn
Qian-fei Wang
1CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2China National Center for Bioinformation, Beijing 100101, China
3University of Chinese Academy of Sciences, Beijing 100049, China
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  • For correspondence: wangqf@big.ac.cn liyy@big.ac.cn
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Abstract

Ex vivo-expanded mesenchymal stem cells (MSCs) have been demonstrated to be a heterogeneous mixture of cells exhibiting varying proliferative, multipotential, and immunomodulatory capacities. However, the exact characteristics of MSCs remain largely unknown. By single-cell RNA sequencing of 61,296 MSCs derived from bone marrow and Wharton’s jelly, we revealed five distinct subpopulations. The developmental trajectory of these five MSC subpopulations were mapped, revealing a differentiation path from stem-like active proliferative cells (APCs) to multipotent progenitor cells, followed by the branching into two paths – adipogenesis or osteochondrogenesis – and subsequent differentiation into unipotent prechondrocytes. The stem-like APCs, expressing the perivascular mesodermal progenitor markers CSPG4/MCAM/NES, uniquely exhibited strong proliferation and stemness signatures. Remarkably, the prechondrocyte subpopulation specifically expressed immunomodulatory genes and was able to suppress activated CD3+ T cell proliferation in vitro, supporting the role of this population in immunoregulation. In summary, our analysis mapped the heterogeneous subpopulations of MSCs and identified two subpopulations with potential functions in self-renewal and immunoregulation. Our findings advance the definition of MSCs by identifying the specific functions of its heterogeneous cellular composition, allowing for more specific and effective MSC application through the purification of its functional subpopulations.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 24, 2021.
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Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells
Chen Zhang, Xueshuai Han, Jingkun Liu, Lei Chen, Ying Lei, Kunying Chen, Jia Si, Tian-yi Wang, Hui Zhou, Xiaoyun Zhao, Xiaohui Zhang, Yihua An, Yueying Li, Qian-fei Wang
bioRxiv 2021.11.24.469676; doi: https://doi.org/10.1101/2021.11.24.469676
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Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells
Chen Zhang, Xueshuai Han, Jingkun Liu, Lei Chen, Ying Lei, Kunying Chen, Jia Si, Tian-yi Wang, Hui Zhou, Xiaoyun Zhao, Xiaohui Zhang, Yihua An, Yueying Li, Qian-fei Wang
bioRxiv 2021.11.24.469676; doi: https://doi.org/10.1101/2021.11.24.469676

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