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01, 2022;32 (1): 38-53.

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

Suwei Gao, Qiang Shi, Yifan Zhang, Guixian Liang, Zhixin Kang, Baofeng Huang, Dongyuan Ma, Lu Wang, Jianwei Jiao, Xiangdong Fang, Cheng-Ran Xu, Longqi Liu, Xun Xu, Berthold Göttgens, Cheng Li, Feng Liu
Author Information
  1. Suwei Gao: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  2. Qiang Shi: School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. ORCID
  3. Yifan Zhang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  4. Guixian Liang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  5. Zhixin Kang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  6. Baofeng Huang: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  7. Dongyuan Ma: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  8. Lu Wang: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  9. Jianwei Jiao: Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. ORCID
  10. Xiangdong Fang: Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
  11. Cheng-Ran Xu: Department of Human Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China. ORCID
  12. Longqi Liu: BGI-ShenZhen, Shenzhen, Guangdong, China.
  13. Xun Xu: BGI-ShenZhen, Shenzhen, Guangdong, China. ORCID
  14. Berthold Göttgens: Department of Haematology, Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  15. Cheng Li: School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China. cheng_li@pku.edu.cn. ORCID
  16. Feng Liu: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. liuf@ioz.ac.cn. ORCID
PMID: 34341490 DOI: 10.1038/s41422-021-00540-7

Abstract

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.

References

Immunity. 2019 Jun 18;50(6):1439-1452.e5 [PMID: 31178352]
Nature. 2018 Nov;563(7731):347-353 [PMID: 30429548]
Urol Oncol. 2011 Jan-Feb;29(1):78-84 [PMID: 19272799]
Biochem Biophys Res Commun. 2012 Nov 23;428(3):354-9 [PMID: 23092738]
Stem Cells Dev. 2016 Apr 15;25(8):575-85 [PMID: 26943017]
Nat Neurosci. 2017 Aug;20(8):1052-1061 [PMID: 28628103]
Stem Cells. 2013 Oct;31(10):2193-204 [PMID: 23818291]
Development. 2016 Apr 15;143(8):1284-9 [PMID: 27095492]
Development. 2006 Oct;133(19):3733-44 [PMID: 16968814]
Immunity. 2015 Apr 21;42(4):665-78 [PMID: 25902481]
Nature. 2019 Oct;574(7778):365-371 [PMID: 31597962]
Blood. 2015 Nov 19;126(21):2383-91 [PMID: 26384355]
Cell. 1990 Jun 15;61(6):953-63 [PMID: 1972037]
Sci Signal. 2016 Oct 25;9(451):ra103 [PMID: 27811141]
Cell. 2019 Dec 12;179(7):1647-1660.e19 [PMID: 31835037]
Immunity. 2018 Aug 21;49(2):326-341.e7 [PMID: 30054204]
Science. 2016 Jul 1;353(6294):78-82 [PMID: 27365449]
Front Immunol. 2015 Sep 22;6:486 [PMID: 26441990]
Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7799-804 [PMID: 20385801]
Syst Synth Biol. 2015 Jun;9(1-2):1-10 [PMID: 25972984]
J Exp Med. 2017 Feb;214(2):529-545 [PMID: 28031476]
Cell Res. 2020 Sep;30(9):763-778 [PMID: 32541867]
Nat Med. 2006 Feb;12(2):240-5 [PMID: 16429146]
J Exp Med. 2019 Jul 1;216(7):1599-1614 [PMID: 31076455]
Science. 2016 Jan 8;351(6269):176-80 [PMID: 26634440]
Annu Rev Immunol. 2015;33:643-75 [PMID: 25861979]
J Mol Endocrinol. 2018 Jul;61(1):T11-T28 [PMID: 29255001]
OMICS. 2012 May;16(5):284-7 [PMID: 22455463]
Semin Immunol. 2015 Dec;27(6):379-87 [PMID: 27021646]
Blood. 2011 Oct 6;118(14):3853-61 [PMID: 21666053]
Science. 2016 Sep 9;353(6304): [PMID: 27492475]
Sci China Life Sci. 2018 Aug;61(8):885-892 [PMID: 29934917]
Blood. 2006 Jul 15;108(2):737-44 [PMID: 16569764]
J Exp Med. 2018 Feb 5;215(2):645-659 [PMID: 29282253]
Cell. 2015 Jan 15;160(1-2):241-52 [PMID: 25594182]
Data Brief. 2016 Jan 08;6:556-61 [PMID: 26909367]
Nat Cell Biol. 2020 Jan;22(1):49-59 [PMID: 31907410]
Blood. 2007 Oct 15;110(8):2889-98 [PMID: 17644732]
Front Med. 2016 Sep;10(3):297-310 [PMID: 27272188]
Nat Biotechnol. 2019 Dec;37(12):1482-1492 [PMID: 31796933]
Histol Histopathol. 2014 Sep;29(9):1077-82 [PMID: 24526457]
Blood. 2004 Apr 1;103(7):2513-21 [PMID: 14592820]
Nature. 2018 Dec;564(7734):119-124 [PMID: 30455424]
Exp Hematol. 1997 Apr;25(4):293-7 [PMID: 9131003]
Cell. 2021 Feb 4;184(3):810-826.e23 [PMID: 33406409]
Exp Hematol. 1996 Apr;24(5):638-48 [PMID: 8605969]
Am J Pathol. 2017 May;187(5):999-1015 [PMID: 28322199]
Exp Hematol. 2019 Oct;78:11-20 [PMID: 31513832]
J Exp Med. 2021 Mar 1;218(3): [PMID: 33151261]
Nat Biotechnol. 2018 Dec 03;: [PMID: 30531897]
Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1056-64 [PMID: 18728224]
Dev Cell. 2017 Aug 21;42(4):349-362.e4 [PMID: 28803829]
Blood. 1994 Oct 15;84(8):2422-30 [PMID: 7919361]
Nature. 2019 Jul;571(7763):117-121 [PMID: 31142833]
Nat Rev Genet. 2020 Sep;21(9):541-554 [PMID: 32467607]
Differentiation. 2019 Mar - Apr;106:9-14 [PMID: 30826473]
Blood. 2000 Apr 1;95(7):2284-8 [PMID: 10733497]
Nature. 2016 May 18;533(7604):487-92 [PMID: 27225119]
Cell Stem Cell. 2010 Aug 6;7(2):186-97 [PMID: 20619763]
Blood. 2010 Jul 29;116(4):544-53 [PMID: 20442369]
Cell. 2013 Aug 29;154(5):1112-1126 [PMID: 23993099]
Cell. 2018 Feb 22;172(5):1091-1107.e17 [PMID: 29474909]
Semin Reprod Med. 2019 Jul;37(4):174-181 [PMID: 31972862]
Cell Stem Cell. 2012 Feb 3;10(2):120-36 [PMID: 22305562]
Nature. 2019 Dec;576(7786):281-286 [PMID: 31776511]
Nature. 2015 Feb 26;518(7540):547-51 [PMID: 25470051]
Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9413-9422 [PMID: 32291340]
Cell Stem Cell. 2012 Nov 2;11(5):701-14 [PMID: 23122293]
Immunity. 2016 May 17;44(5):1162-76 [PMID: 27156384]
Biochem Biophys Res Commun. 2013 Jan 4;430(1):20-5 [PMID: 23149415]
Blood. 2010 Nov 25;116(22):4444-55 [PMID: 20693433]
Cell Stem Cell. 2010 Aug 6;7(2):174-85 [PMID: 20619762]
Nat Protoc. 2020 Apr;15(4):1484-1506 [PMID: 32103204]
Cell Res. 2020 Dec;30(12):1109-1126 [PMID: 32690901]
Front Endocrinol (Lausanne). 2018 Apr 09;9:117 [PMID: 29686648]

Grants

  1. G0900951/Medical Research Council
  2. MC_PC_17230/Medical Research Council
  3. MR/S036113/1/Medical Research Council

MeSH Term

Animals
Endothelial Cells
Hematopoiesis
Hematopoietic Stem Cells
Liver
Mice
Transcriptome
Journal Article Research Support, Non-U.S. Gov't

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