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Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats
Author(s) -
Rudolph K. Lenhard,
Trautwein Christian,
Kubicka Stefan,
Rakemann Tim,
Bahr Matthias J.,
Sedlaczek Nick,
Schuppan Detlef,
Manns Michael P.
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300502
Subject(s) - in situ hybridization , hepatocyte , matrix metalloproteinase , rna , hepatic stellate cell , extracellular matrix , downregulation and upregulation , northern blot , liver regeneration , microbiology and biotechnology , messenger rna , biology , extracellular , chemistry , medicine , endocrinology , in vitro , biochemistry , regeneration (biology) , gene
Little is known about the modulation of the extracellular matrix (ECM) during liver regeneration. We studied the temporospatial expression of procollagens and of matrix metalloproteinases (MMPs) and their physiological antagonists, the tissue inhibitors of metalloproteinases (TIMPs) after two‐thirds partial hepatectomy (PH) by Northern blot analysis and in situ hybridization. The entry of hepatocytes into the S‐phase at 24 hours after PH was accompanied by a peak (sixfold induction) of hepatic TIMP‐1 RNA levels that steadily declined thereafter to reach normal levels 144 hours after PH. Moderate MMP‐2 and TIMP‐2 RNA levels remained constant up to 144 hours after PH, and MMP‐1 and ‐13 RNA were always undetectable. In situ hybridization showed a dramatic upregulation of TIMP‐1 RNA transcripts in mesenchymal cells of portal, perisinusoidal and, to a lesser extent, pericentral areas. In contrast, scattered hepatocytes represented only a minor fraction (below 10%) of TIMP‐1 RNA positive cells. When hepatocytes stopped DNA synthesis at 72 hours after PH, an upregulation of procollagen α1(I) and α2(III) transcripts was observed paralleled by threefold increased PIIINP levels in the sera. Our data reveal a tightly regulated program of de novo matrix synthesis after PH. Whereas interstitial procollagens appear to participate in the induction and maintenance of the quiescent hepatocyte phenotype, the early and localized expression of TIMP‐1 indicates a role unrelated to its function as a general MMP‐antagonist, e.g. , as a growth promoting agent for hepatocytes.