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

Cell Research volume 33, pages 448–463 (2023)Cite this article

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Abstract

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.

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Fig. 1: Single-cell transcriptomic and epigenetic analysis of HEC/HSPC heterogeneity.
Fig. 2: Lineage tracing of spi2+ HECs.
Fig. 3: STRT-seq of spi2+ lineages and the stress-induced response of spi2+ HEC by LPS treatments.
Fig. 4: spi2 is required for the specification of L/M-HSPCs.
Fig. 5: Transcriptional activation of genes related to artery development and suppression of genes related to immune homeostasis in spi2-KD HECs.
Fig. 6: Spi2 regulates lymphoid/myeloid HSPC fates by directly activating the transcription of master hematopoietic TFs and repressing that of the master endothelial TFs in HECs.
Fig. 7: SPI1 inhibition impairs human L/M-HSPC generation.

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Data availability

The omics datasets generated in the present study are available at the Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/) under the accession number GSE186427.

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Acknowledgements

We thank laboratory members for helpful discussions and critical reading of the paper. We would like to express our gratitude to Dr. Jiulin Du for sharing Tg(UAS:GFP), Tg(UAS:mCherry) and Tg(UAS:Kaede) lines. This work was supported by grants from the National Key R&D Program of China (2018YFA0800200 and 2018YFA0801000), the Strategic Priority Research Program of the Chinese Academy of Sciences, China (XDA16010207), the National Natural Science Foundation of China (31830061 and 32030032) and the Open Research Program of State Key Laboratory of Membrane Biology (2021KF07).

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  1. These authors contributed equally: Jun Xia, Mengyao Liu.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Jun Xia, Shicheng Liu, Dongyuan Ma & Feng Liu

  2. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

    Jun Xia, Shicheng Liu, Dongyuan Ma & Feng Liu

  3. University of Chinese Academy of Sciences, Beijing, China

    Jun Xia, Shicheng Liu, Dongyuan Ma & Feng Liu

  4. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Mengyao Liu, Caiying Zhu, Lanlan Ai, Ping Zhu & Lu Wang

  5. School of Life Sciences, Shandong University, Qingdao, Shandong, China

    Feng Liu

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Contributions

J.X. carried out the zebrafish experiments; M.L. preformed the bioinformatic analysis under the guidance of L.W.; C.Z. and L.A. performed STRT-seq analysis under the guidance of P.Z.; S.L. performed human iPSC hematopoietic cell differentiation assay; D.M. contributed to the editing of the manuscript; J.X. and F.L. conceived the project, analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lu Wang or Feng Liu.

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Xia, J., Liu, M., Zhu, C. et al. Activation of lineage competence in hemogenic endothelium precedes the formation of hematopoietic stem cell heterogeneity. Cell Res 33, 448–463 (2023). https://doi.org/10.1038/s41422-023-00797-0

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