Abstract
Hepatic stellate cells (HSCs), vitamin A-storing liver pericytes, undergo myofibroblastic trans-differentiation or "activation" to participate in liver wound healing. This cellular process involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ). Necdin, a melanoma antigen family protein, promotes neuronal and myogenic differentiation while inhibiting adipogenesis. The present study demonstrates that necdin is selectively expressed in HSCs among different liver cell types and induced during their activation in vitro and in vivo. Silencing of necdin with adenovirally expressed shRNA, reverses activated HSCs to quiescent cells in a manner dependent on PPARγ and suppressed canonical Wnt signaling. Promoter analysis, site-directed mutagenesis, and chromatin immunoprecipitation demonstrate that Wnt10b, a canonical Wnt induced in activated HSCs, is a direct target of necdin. Necdin silencing abrogates three epigenetic signatures implicated in repression of PPARγ: increased MeCP2 (methyl CpG binding protein 2) and HP-1α co-repressor recruitments to Pparγ promoter and enhanced H3K27 dimethylation at the exon 5 locus, again in a manner dependent on suppressed canonical Wnt. These epigenetic effects are reproduced by antagonism of canonical Wnt signaling with Dikkopf-1. Our results demonstrate a novel necdin-Wnt pathway, which serves to mediate antiadipogenic HSC trans-differentiation via epigenetic repression of PPARγ.
Highlights
Hepatic stellate cells (HSCs)2 are desmin-positive mesenchymal cells located in the subendothelial space of hepatic sinusoids
Necdin Is Induced in Activated HSCs—we examined the expression of necdin in culture-activated HSCs
HSCs were isolated from rats with cholestatic liver fibrosis induced by bile duct ligation (BDL) or those with hepatotoxic liver fibrosis resulting from repetitive injections of carbon tetrachloride (CCl4), as well as their controls: rats with sham-operation and those injected with oil, the vehicle for CCl4
Summary
Hepatic stellate cells (HSCs) are desmin-positive mesenchymal cells located in the subendothelial (perisinusoidal) space of hepatic sinusoids. Major classes of mediators are identified for HSC trans-differentiation, including soluble factors (cytokines, hormones, and lipid mediators), reactive oxygen species, and altered extracellular matrix milieu [1], the fundamental understanding of cell lineage and cell fate regulation of HSCs is elusive In this regard, Asahina et al [2] has demonstrated recently the mesenchymal origin of fetal HSCs and “submesothelial cell” as a potential precursor for HSCs. Intriguingly, HSCs express markers for cell types derived from multipotent mesenchymal progenitor cells such as neural cells, chondrocytes, osteoblasts, smooth muscle cells, and adipocytes [3], suggesting the HSC lineage may be located somewhere within these mesenchymal lineages. Some of these cell fate regulations are mediated at least in part via the interaction of necdin with Wnt promoter through homeodomain proteins such as Msx and Dlx2 [17, 21]
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