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Dissecting endothelial to haematopoietic stem cell transition by single-cell transcriptomic and functional analyses

By Siyuan Hou, Zongcheng Li, Xiaona Zheng, Yun Gao, Ji Dong, Yanli Ni, Xiaobo Wang, Yunqiao Li, Xiaochen Ding, Zhilin Chang, Shuaili Li, Yuqiong Hu, Xiaoying Fan, Yu Hou, Lu Wen, Bing Liu, Fuchou Tang, Yu Lan

Posted 20 Jan 2020
bioRxiv DOI: 10.1101/2020.01.18.910356 (published DOI: 10.1038/s41422-020-0300-2)

Hematopoietic stem cells (HSCs) in adults are believed to be born from hemogenic endothelial cells (HECs) in mid-gestational mouse embryos. Due to rare and transient nature, the HSC-competent ECs have never been stringently identified and accurately captured, let alone their genuine vasculature precursors. Here, we firstly used high-precision single-cell transcriptomics to unbiasedly examine relevant EC populations at continuous developmental stages and transcriptomically identified putative HSC-primed HECs. Combining computational prediction and in vivo functional validation, we precisely captured HSC-competent HECs by newly constructed Neurl3-EGFP reporter mouse model, and realized enrichment further by surface marker combination. Surprisingly, endothelial-haematopoietic bi-potential was rarely but reliably witnessed in culture of single HECs. Noteworthy, primitive vascular ECs experienced two-step fate choices to become HSC-primed HECs, resolving 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.

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