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Review
. 2012 Mar;27 Suppl 2(Suppl 2):94-8.
doi: 10.1111/j.1440-1746.2011.07022.x.

Morphogens and hepatic stellate cell fate regulation in chronic liver disease

Hidekazu Tsukamoto  1 , Nian-Ling Zhu, Jiaohong Wang, Kinji Asahina, Keigo Machida
Affiliations
Review

Morphogens and hepatic stellate cell fate regulation in chronic liver disease

Hidekazu Tsukamoto et al. J Gastroenterol Hepatol. 2012 Mar.

Abstract

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.

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Conflict of interest statement

Conflict of interest: no conflict of interest has been declared by the authors.

Figures

Figure 1
Figure 1
The transcriptional regulation required for adipocyte differentiation is also essential for hepatic stellate cell (HSC) differentiation or quiescence. Morphogens, necdin, Wnt and Shh positively cross-interact and epigenetically repress the master adipogenic gene Pparγ involving the methyl-CpG binding protein MeCP2 and polycomb repressive complex 2 (PRC2) H3K27 methyltransferase, EZH2.
Figure 2
Figure 2
The activation of hepatic stellate cells, which is in part caused by the epigenetic repression of Pparγ by morphogens, may play different roles in the evolution of chronic liver disease from liver fibrosis, regeneration and cancer. Mediators shown are representatives: coll, collagens; TIMP, tissue inhibitor of metalloptroteinase; PTN, pleiotrophin, FGF, fibroblast growth factor, HGF, hepatocyte growth factor; p75NTR, p75 neurotrophin receptor; VEGF, vascular endothelial growth factor.
See this image and copyright information in PMC

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