Volume 33, No 6, Jun 2023

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

Volume 33 Issue 6, June 2023: 448-463

ORIGINAL ARTICLES

Activation of lineage competence in hemogenic endothelium precedes the formation of hematopoietic stem cell heterogeneity

Jun Xia^1,2,3,† , Mengyao Liu^4,† , Caiying Zhu⁴ , Shicheng Liu^1,2,3 , Lanlan Ai⁴ , Dongyuan Ma^1,2,3 , Ping Zhu⁴ , Lu Wang^4,* , Feng Liu^1,2,3,5,*

¹State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
²Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
³University of Chinese Academy of Sciences, Beijing, China
⁴State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
⁵School of Life Sciences, Shandong University, Qingdao, Shandong, China
^†These authors contributed equally: Jun Xia, Mengyao Liu
Correspondence: Lu Wang(wanglu1@ihcams.ac.cn)Feng Liu(liuf@ioz.ac.cn)

Hematopoietic stem and progenitor cells (HSPCs) are considered as a heterogeneous population, but precisely when, where and how HSPC heterogeneity arises remain largely unclear. Here, using a combination of single-cell multi-omics, lineage tracing and functional assays, we show that embryonic HSPCs originate from heterogeneous hemogenic endothelial cells (HECs) during zebrafish embryogenesis. Integrated single-cell transcriptome and chromatin accessibility analysis demonstrates transcriptional heterogeneity and regulatory programs that prime lymphoid/myeloid fates at the HEC level. Importantly, spi2+ HECs give rise to lymphoid/myeloid-primed HSPCs (L/M-HSPCs) and display a stress-responsive function under acute inflammation. Moreover, we uncover that Spi2 is required for the formation of L/M-HSPCs through tightly controlling the endothelial-to-hematopoietic transition program. Finally, single-cell transcriptional comparison of zebrafish and human HECs and human induced pluripotent stem cell-based hematopoietic differentiation results support the evolutionary conservation of L/M-HECs and a conserved role of SPI1 (spi2 homolog in mammals) in humans. These results unveil the lineage origin, biological function and molecular determinant of HSPC heterogeneity and lay the foundation for new strategies for induction of transplantable lineage-primed HSPCs in vitro.

https://doi.org/10.1038/s41422-023-00797-0

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