Volume 32, No 1, Jan 2022

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

Volume 32 Issue 1, January 2022: 38-53

ORIGINAL ARTICLES

Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics

Suwei Gao^1,2,3,† , Qiang Shi^4,† , Yifan Zhang^1,2,3 , Guixian Liang^1,2,3 , Zhixin Kang^1,2,3 , Baofeng Huang^1,2,3 , Dongyuan Ma^1,2 , Lu Wang⁵ , Jianwei Jiao^2,3,6 , Xiangdong Fang^2,3,7,8 , Cheng-Ran Xu^9,10 , Longqi Liu^11,12 , Xun Xu^11,13 , Berthold Göttgens¹⁴ , Cheng Li^4,* , Feng Liu^1,2,3,*

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
⁴School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China
⁵State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
⁶State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
⁷CAS Key Laboratory of Genome Science & Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
⁸Beijing Key Laboratory of Genome and Precision Medicine Technologies, Beijing, China
⁹Department of Human Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China
¹⁰Peking–Tsinghua Center for Life Sciences, Peking University, Beijing, China
¹¹BGI-ShenZhen, Shenzhen, Guangdong, China
¹²Shenzhen Bay Laboratory, Shenzhen, Guangdong, China
¹³Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, Guangdong, China
¹⁴Department of Haematology, Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
^†These authors contributed equally: Suwei Gao, Qiang Shi
Correspondence: Cheng Li(cheng_li@pku.edu.cn)Feng Liu(liuf@ioz.ac.cn)

Limited knowledge of cellular and molecular mechanisms underlying hematopoietic stem cell and multipotent progenitor (HSC/MPP) expansion within their native niche has impeded the application of stem cell-based therapies for hematological malignancies. Here, we constructed a spatiotemporal transcriptome map of mouse fetal liver (FL) as a platform for hypothesis generation and subsequent experimental validation of novel regulatory mechanisms. Single-cell transcriptomics revealed three transcriptionally heterogeneous HSC/MPP subsets, among which a CD93-enriched subset exhibited enhanced stem cell properties. Moreover, by employing integrative analysis of single-cell and spatial transcriptomics, we identified novel HSC/MPP ‘pocket-like’ units (HSC PLUS), composed of niche cells (hepatoblasts, stromal cells, endothelial cells, and macrophages) and enriched with growth factors. Unexpectedly, macrophages showed an 11-fold enrichment in the HSC PLUS. Functionally, macrophage–HSC/MPP co-culture assay and candidate molecule testing, respectively, validated the supportive role of macrophages and growth factors (MDK, PTN, and IGFBP5) in HSC/MPP expansion. Finally, cross-species analysis and functional validation showed conserved cell–cell interactions and expansion mechanisms but divergent transcriptome signatures between mouse and human FL HSCs/MPPs. Taken together, these results provide an essential resource for understanding HSC/MPP development in FL, and novel insight into functional HSC/MPP expansion ex vivo.

https://doi.org/10.1038/s41422-021-00540-7

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