Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells

Authors

  • Mark Johnson,

    1. Division of Biochemistry, Rush Graduate College, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60610
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  • George Koukoulis,

    1. Department of Pathology, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60610
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  • Kunio Matsumoto,

    1. Department of Pathology, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60610
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  • Toshikazu Nakamura,

    1. Department of Biology, Faculty of Science, Kyushu University, Fukuoka 812, Japan
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  • Anand Iyer

    Corresponding author
    1. Department of Medicine, Section of Oncology, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60610
    2. Department of Biochemistry, Rush–Presbyterian–St. Luke's Medical Center, Chicago, Illinois 60610
    • Department of Biochemistry, Rush–Presbyterian–St. Luke's Medical Center, 1753 W. Congress Parkway, Chicago, IL 60610
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Abstract

Hepatocyte growth factor is the most potent mitogen known for hepatocytes, and increasing evidence suggests that hepatocyte growth factor plays an important role in liver regeneration. However, hepatocytes are not the only liver epithelial cell population that proliferates during regeneration. Experimental and clinical data indicate that the regenerative liver response also includes the participation of nonparenchymal epithelial cells. The possible role of hepatocyte growth factor in this nonparenchymal epithelial cell regenerative response has not been explored. We studied the effects of hepatocyte growth factor with a model of two normal mouse nonparenchymal epithelial cell–derived cell lines with varying differentiation potentials. Addition of hepatocyte growth factor induced mitogenesis and scattering of colonies growing on culture dishes in both cell lines. Furthermore, hepatocyte growth factor was found to exert a profound morphogenic effect on cells growing in collagen matrixes. Hepatocyte growth factor–treated embryonic BNL CL.2 cell colonies developed elaborately branching elongated cords with only minimal tubularization. Hepatocyte growth factor–treated postnatal NMuLi cell colonies developed a network of anastomosing tubules with wide lumens. These morphological changes were not inhibitable by transforming growth factor-β and were not induced by other hepatocellular growth factors including epidermal growth factor, transforming growth factor-α, acidic fibroblast growth factor and insulin. Histological sections of the hepatocyte growth factor–treated BNL CL.2 cell colonies resembled neocholangioles, believed to include facultative stem cells, which proliferate after submassive and massive hepatic necrosis. Sections of hepatocyte growth factor–treated NMuLi colonies resembled ductules proliferating in biliary tract obstruction from a wide variety of causes. This work represents the first examples of hepatocyte growth factor–induced mitogenesis, scattering and morphogenesis in the same cell lines. More important, our data suggest that hepatocyte growth factor mediates liver response to injury not only by acting on hepatocytes but also by exerting mitogenic and morphogenic influences on nonparenchymal epithelial cell components. (HEPATOLOGY 1993;17:1052–1061.)

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