Volume 30, No 5, May 2020

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

Volume 30 Issue 5, May 2020: 376-392   |  Open Access

ORIGINAL ARTICLES

Embryonic endothelial evolution towards first hematopoietic stem cells revealed by single-cell transcriptomic and functional analyses

Siyuan Hou^1,2,3 , Zongcheng Li² , Xiaona Zheng⁴ , Yun Gao⁵ , Ji Dong⁵ , Yanli Ni² , Xiaobo Wang⁴ , Yunqiao Li⁴ , Xiaochen Ding⁴ , Zhilin Chang⁴ , Shuaili Li⁴ , Yuqiong Hu⁵ , Xiaoying Fan⁵ , Yu Hou⁵ , Lu Wen^5,6 , Bing Liu^1,2,* , Fuchou Tang^5,6,7,* , Yu Lan^1,8,*

¹Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
²State Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
³Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong 510632, China
⁴State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100071, China
⁵Beijing Advanced Innovation Center for Genomics and Biomedical Institute for Pioneering Investigation via Convergence, College of Life Sciences, Peking University, Beijing 100871, China
⁶Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
⁷Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
⁸Guangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL), Guangzhou, Guangdong 510530, China
These authors contributed equally: Siyuan Hou, Zongcheng Li, Xiaona Zheng, Yun Gao, Ji Dong, Yanli Ni Correspondence: Bing Liu(bingliu17@yahoo.com)Fuchou Tang(tangfuchou@pku.edu.cn)Yu Lan(rainyblue_1999@126.com)

Hematopoietic stem cells (HSCs) in adults are believed to be born from hemogenic endothelial cells (HECs) in mid-gestational embryos. Due to the rare and transient nature, the HSC-competent HECs have never been stringently identified and accurately captured, let alone their genuine vascular precursors. Here, we first used high-precision single-cell transcriptomics to unbiasedly examine the relevant EC populations at continuous developmental stages with intervals of 0.5 days from embryonic day (E) 9.5 to E11.0. As a consequence, we transcriptomically identified two molecularly different arterial EC populations and putative HSC-primed HECs, whose number peaked at E10.0 and sharply decreased thereafter, in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region. Combining computational prediction and in vivo functional validation, we precisely captured HSC-competent HECs by the newly constructed Neurl3-EGFP reporter mouse model, and realized the enrichment further by a combination of surface markers (Procr+Kit+CD44+, PK44). Surprisingly, the endothelial-hematopoietic dual potential was rarely but reliably witnessed in the cultures of single HECs. Noteworthy, primitive vascular ECs from E8.0 experienced two-step fate choices to become HSC-primed HECs, namely an initial arterial fate choice followed by a hemogenic fate conversion. This finding resolves several previously observed contradictions. Taken together, comprehensive understanding of endothelial evolutions and molecular programs underlying HSC-primed HEC specification in vivo will facilitate future investigations directing HSC production in vitro.

https://doi.org/10.1038/s41422-020-0300-2

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