Morphogens and hepatic stellate cell fate regulation in chronic liver disease.
Hepatic stellate cells (HSC) are the liver mesenchymal cell type which responds to hepatocellular damage and participates in wound healing. Although HSC myofibroblastic trans-differentiation (activation) is implicated in excessive extracellular matrix deposition, molecular understanding of this phenotypic switch from the viewpoint of cell fate regulation is limited. Recent studies demonstrate the roles of anti-adipogenic morphogens (Wnt, Necdin, Shh) in epigenetic repression of the HSC differentiation gene Pparγ as a causal event in HSC activation. These morphogens have positive cross-interactions which converge to epigenetic repression of Pparγ involving the methyl-CpG binding protein MeCP2. However, these morphogens expressed by activated HSC may also participate in cross-talk between HSC and hepatoblasts/hepatocytes to support liver regeneration, and their aberrant regulation may contribute to liver tumorigenesis. Implications of HSC-derived morphogens in these possibilities are discussed.
Southern California Research Center for ALPD and Cirrhosis, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. htsukamo@usc.edu
Hidekazu
H
Tsukamoto
Nian-Ling
NL
Zhu
Jiaohong
J
Wang
Kinji
K
Asahina
Keigo
K
Machida
D050156:Adipogenesis; D000818:Animals; D002908:Chronic Disease; D044127:Epigenesis, Genetic; D053823:Hedgehog Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D051153:Wnt Proteins; C069766:necdin