Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development

Authors

  • Kinji Asahina,

    Corresponding author
    1. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis and Department of Pathology, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
    • Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR 402, Los Angeles, CA 90033-9141
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    • fax: 323-442-3126.

  • Shirley Y. Tsai,

    1. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis and Department of Pathology, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
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  • Peng Li,

    1. Institute for Genetic Medicine, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
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  • Mamoru Ishii,

    1. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
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  • Robert E. Maxson Jr.,

    1. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
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  • Henry M. Sucov,

    1. Institute for Genetic Medicine, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
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  • Hidekazu Tsukamoto

    1. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis and Department of Pathology, Norris Comprehensive Cancer Center and Hospital, Keck School of Medicine of the University of Southern California
    2. Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA
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  • Potential conflict of interest: Nothing to report.

Abstract

The knowledge concerning fetal hepatic stellate cells (HSCs) is scarce, and their cell lineage and functions are largely unknown. The current study isolated fetal liver mesenchymal cells from a mouse expressing β-galactosidase under the control of Msx2 promoter by fluorescence-activated cell sorting (FACS) and surveyed marker genes by microarray analysis. Based on the location and immunostaining with conventional and newly disclosed markers, we have identified three distinct populations of fetal liver mesenchymal cells expressing both desmin and p75 neurotrophin receptor (p75NTR): HSCs in the liver parenchyma; perivascular mesenchymal cells expressing α-smooth muscle actin (α-SMA); and submesothelial cells associated with the basal lamina beneath mesothelial cells and expressing activated leukocyte cell adhesion molecule (ALCAM) and platelet-derived growth factor receptor α. A transitional cell type from the submesothelial cell phenotype to fetal HSCs was also identified near the liver surface. Mesothelial cells expressed podoplanin and ALCAM. Ki-67 staining showed that proliferative activity of the submesothelial cells is higher than that of mesothelial cells and transitional cells. Using anti-ALCAM antibodies, submesothelial and mesothelial cells were isolated by FACS. The ALCAM+ cells expressed hepatocyte growth factor and pleiotrophin. In culture, the ALCAM+ cells rapidly acquired myofibroblastic morphology and α-SMA expression. The ALCAM+ cells formed intracellular lipid droplets when embedded in collagen gel and treated with retinol, suggesting the potential for ALCAM+ cells to differentiate to HSCs. Finally, we demonstrated that fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are all derived from mesoderm by using MesP1-Cre and ROSA26 reporter mice. Conclusion: Fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are mesodermal in origin, and ALCAM+ submesothelial cells may be a precursor for HSCs in developing liver. (HEPATOLOGY 2009.)

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