Hepatic Stellate Cells: Multifunctional mesenchymal cells of the Liver

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Κανδάκη Καλογιάννης
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1 Nagoya Med. J., 137 Hepatic Stellate Cells: Multifunctional mesenchymal cells of the Liver KAZUO IKEDA Department of Anatomy and Cell Biology, Graduate School of Medical Sciences, Nagoya City University Hepatic stellate cells constitute the sinusoidal wall as liver specific pericytes and store vitamin A-associated lipid droplets. In liver injury, hepatic stellate cells undergo activation proliferation and migration and generate a large amount of extracellular matrix materials. Stellate cells activation is an important event in pathology of liver diseases because it is believed to play roles in the development of fibrosis. The analysis of genes associated with stellate cells activation could provide a clue to the molecular mechanism and gene therapy of fibrotic liver disease. Although the molecules characteristic of activated hepatic stellate cells have been extensively studied over a decade, here we introduce the data from the suppressive subtraction hybridization, the homology PCR of receptor tyrosine kinase, microrna array analysis we employed. TNP- TGF-β 137

2 138 Suppression Subtractive Hybridization Receptor Tyrosine Kinase Homology PCR micro RNA mrna Suppression subtractive hybridization α-smooth muscle actin laminin β entactin oxidative LDL bp bp cdna in vivo SSH Receptor tyrosine kinase RTK kinase primer PDGFR RTK Homology PCR Discoidin Domain Receptor DDR DDR DDR DDR DDR DDR DDR DDR DDR DDR DDR α PDGFR DDR DDR

3 139 DDR DDR DDR Src Src DDR Modified Yeast two hybrid Bait DDR cytoplasmic domain cdna prey Src yeast Shc adaptor protein kda kda kda CH SH DDR Shc DDR N-P-X-Y Shc PTB Shc DDR cytoplasmic domain PTB domain CH SH Src Shc DDR DDR Shc DDR Shc DDR Shc Src kinase PP SU Src DDR Y tyrosine site DDR RTK HSC-T DDR ATP DDR H DDR DDR DDR RTK DDR MMP- HT- HSC-T MMP- MMP- MMP- DDR MMP- DDR DDR HSC-T cell Western Blot zymography assay DDR MMP- DDR MMP- MMP- invasion assay DDR DDR control RNA RNA RNA RNA

4 140 RNA micro RNA DNA RNA RNA micro RNA micro RNA micro RNA micro RNA micro RNA micro RNA micro RNA mir- mir- mir- precursor micro RNA seqences micro RNA Hepatocytes function Ikeda K, Kawada N, Wang YQ, et al: Expression of cellular prion protein in activated hepatic stellate cells. Am J Pathol. : -, Olaso E, Ikeda K, Eng FJ et al: DDR receptor promotes MMP- -mediated proliferation and invasion by hepatic stellate cells. J Clin Invest. : -, Ikeda K, Wang LH, Torres R et al: Discoidin domain receptor interacts with Src and Shc following its activation by type I collagen. J Biol Chem. : -, Wang YQ, Ikeda K, Ikebe T, et al: Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP- in rats. Hepatology. : -, Okuno M, Akita K, Moriwaki H, et al: Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta. Gastroenterology. : -, Inagaki Y, Kushida M, Higashi K, et al: Cell typespecific intervention of transforming growth factor beta/smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology. : -, Kinoshita K, Iimuro Y, Fujimoto J, et al: Targeted and regulable expression of transgenes in hepatic stellate cells and myofibroblasts in culture and in vivo using an adenoviral Cre/loxP system to antagonise hepatic fibrosis. Gut. : -, Alves, F., Vogel, W., Mossie, K et al: Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene. : -, Labrador JP, Azcoitia V, Tuckermann J et al: The collagen receptor DDR regulates proliferation and its elimination leads to dwarfism. EMBO Rep. : -, Vogel W: Discoidin domain receptors: structural relations and functional implications. FASEB J. Suppl: S -, Olaso E, Labrador JP, Wang L et al: Discoidin domain receptor regulates fibroblast proliferation and migration through the extracellular matrix in

5 141 association with transcriptional activation of matrix metalloproteinase-. J Biol Chem. : -,

6 142

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