| Co-Investigator(Kenkyū-buntansha) |
TOMITA Yumiko Institute for Enzyme Research, University of Tokushima, Research Assistant, 助手 (00089913)
TANAKA Keiji Institute for Enzyme Research, University of Tokushima, Research Assistant, 助手 (10108871)
NODA Chiseko Institute for Enzyme Research, University of Tokushima, Assistant Professor, 助教授 (40035506)
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| Research Abstract |
Mechanisms of diverse functions and active regeneration of liver were studied using primary cultured hepatocytes with special reference to liver tissue architecture.
(1) A new hepatocyte growth factor(HGF) was purified from rat platelets and its subunit structure was analyzed. It is a heterodimer consisting small(34 kDa) and large(69 kDa) subunits. Recently HGF was found not only in platelets, but also in various rat tissues and HGF activity increased in non-parenchymal liver cells and serum after administration of hepatotoxins.
(2) Hepatocyte growth was inhibited by addition of either transforming growth factor(TGF)-beta or interleukin(IL)-1beta, -6. These inhibitions are cell-density dependent;Effect of TGF-beta is strong at low cell density, while that of IL-1beta is reverse. Addition of cAMP or TPA together with HGF enhanced hepatocyte growth much more than HGF alone, but stimulatory effect of cAMP was high at low cell density and cAMP became inhibitory at high cell density. TPA was
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stimulatory only at high cell density.
(3) Crude TGF-beta released from platelets was inactive, but activated in test tube by acid or high concentration of urea. It was found that activation of latent TGF-beta is due to dissociation of two neutralizing proteins from TGF-beta. Small protein(39 kDa) was identified as a pro-part of precursor of mature TGF-beta. Large protein(110 kDa) was purified and found to contain several EGF like domains, but complete structure is still unknown. It is also still unknown how latent TGF-beta is activated physiologically.
(4) Neonatal rat hepatocytes in culture can grow autonomously and do not express tryptophan oxygenase, a marker of differentiation of liver. However, contact with mature hepatocytes inhibited growth of neonatal hepatocytes and induced differentiation.
These results indicate that mature liver functions and growth are regulated reciprocally by cell contact among hepatocytes, Kupffer cell and endothelial cells and architecture of liver tissue is very important. Less
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