Human Fetal Hepatic Progenitor Cells Are Distinct from, but Closely Related to, Hematopoietic Stem/Progenitor Cells§

Authors

  • Qingfeng Chen,

    1. Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore
    2. Infrastructure, Technology and Translational Division, Institute of Molecular and Cell Biology, ASTAR, Singapore, Singapore
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  • Maroun Khoury,

    1. Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore
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  • Gino Limmon,

    1. Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore
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  • Mahesh Choolani,

    1. Experimental Fetal Medicine Group, Department of Obstetrics & Gynaecology, National University of Singapore, Singapore, Singapore
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  • Jerry K.Y. Chan,

    1. Experimental Fetal Medicine Group, Department of Obstetrics & Gynaecology, National University of Singapore, Singapore, Singapore
    2. Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore
    3. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore
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  • Jianzhu Chen

    Corresponding author
    1. Infectious Disease Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore, Singapore
    2. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    • Koch Institute for Integrative Cancer Research, MIT, 76-261, 77 Massachusetts Avenue, Cambridge, Massachusetts 02142, USA
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    • Telephone: 617-258-6173; Fax: 617-258-6172


  • Author contributions: Q.C.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript preparation; M.K.: data analysis and interpretation and manuscript preparation; G.L.: data analysis and interpretation; M.C.: provision of study materials and clinical samples; J.KY.C.: provision of study materials and clinical samples and manuscript preparation; J.C.: conception and design, data analysis and interpretation, and manuscript preparation.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS February 13, 2013.

Abstract

Much controversy surrounds the identity and origin of human hepatic stem and progenitor cells in part because of a lack of small animal models in which the developmental potential of isolated candidate cell populations can be functionally evaluated. We show here that adoptive transfer of CD34+ cells from human fetal liver into sublethally irradiated NOD-SCID Il2rg−/− (NSG) mice leads to an efficient development of not only human hematopoietic cells but also human hepatocyte-like cells in the liver of the recipient mice. Using this simple in vivo assay in combination with cell fractionation, we show that CD34+ fetal liver cells can be separated into three distinct subpopulations: CD34hiCD133hi, CD34loCD133lo, and CD34hiCD133neg. The CD34hiCD133hi population contains hematopoietic stem/progenitor cells (HSPCs) as they give rise to T cells, B cells, NK cells, dendritic cells, and monocytes/macrophages in NSG mice and colony-forming unit (CFU)-GEMM cells in vitro. The CD34loCD133lo population does not give rise to hematopoietic cells, but reproducibly generates hepatocyte-like cells in NSG mice and in vitro. The CD34hiCD133neg population only gives rise to CFU-GM and burst-forming unit-erythroid in vitro. Furthermore, we show that the CD34loCD133lo cells express hematopoietic, hepatic, and mesenchymal markers, including CD34, CD133, CD117, epithelial cell adhesion molecule, CD73, albumin, α-fetal protein, and vimentin and transcriptionally are more closely related to HSPCs than to mature hepatocytes. These results show that CD34loCD133lo fetal liver cells possess the hepatic progenitor cell properties and that human hepatic and hematopoietic progenitor cells are distinct, although they may originate from the same precursors in the fetal liver. STEM Cells 2013;31:1160–1169

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