Volume 31, No 7, Jul 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 7, July 2021: 742-757   |  Open Access

ORIGINAL ARTICLES

Dissecting human embryonic skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses

Jian He¹ , Jing Yan¹ , Jianfang Wang² , Liangyu Zhao³ , Qian Xin¹ , Yang Zeng⁴ , Yuxi Sun⁵ , Han Zhang⁶ , Zhijie Bai¹ , Zongcheng Li⁴ , Yanli Ni⁴ , Yandong Gong⁴ , Yunqiao Li¹ , Han He¹ , Zhilei Bian⁷ , Yu Lan^8,9 , Chunyu Ma¹⁰ , Lihong Bian¹⁰ , Heng Zhu^11,* , Bing Liu^1,4,8,* , Rui Yue^2,*

¹State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100071, China
²Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
³Department of Orthopedics, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
⁴State Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
⁵Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
⁶Department of Transfusion, Daping Hospital, Army Military Medical University, Chongqing 400042, China
⁷Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
⁸Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
⁹Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, Guangdong 510530, China
¹⁰Department of Gynecology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
¹¹Beijing Institute of Radiation Medicine, Beijing 100850, China
These authors contributed equally: Jian He, Jing Yan, Jianfang Wang, Liangyu Zhao, Qian Xin Correspondence: Heng Zhu(zhudingdingabc@163.com)Bing Liu(bingliu17@yahoo.com)Rui Yue(ryue@tongji.edu.cn)

Human skeletal stem cells (SSCs) have been discovered in fetal and adult long bones. However, the spatiotemporal ontogeny of human embryonic SSCs during early skeletogenesis remains elusive. Here we map the transcriptional landscape of human limb buds and embryonic long bones at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, and aligned them along the proximal–distal and anterior–posterior axes using known marker genes. Osteo-chondrogenic progenitors first appeared in the core limb bud mesenchyme, which give rise to multiple populations of stem/progenitor cells in embryonic long bones undergoing endochondral ossification. Importantly, a perichondrial embryonic skeletal stem/progenitor cell (eSSPC) subset was identified, which could self-renew and generate the osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSPCs are marked by the adhesion molecule CADM1 and highly enriched with FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional networks were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.

https://doi.org/10.1038/s41422-021-00467-z

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