Dataset Information

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.

ABSTRACT: Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in ? smooth muscle actin (?SMA)+ cells after partial hepatectomy (PH).?SMA-Cre-ER(T2)×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96?h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, ?SMA-Cre-ER(T2)×ROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72?h post-PH were analysed for YFP by flow cytometric analysis (FACS).Post-PH, VEH-?SMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-?SMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-?SMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48-72?h after PH, indicating that liver epithelial cells were derived from ?SMA-YFP+ cells.Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.

SUBMITTER: Swiderska-Syn M

PROVIDER: S-EPMC4006344 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.

Swiderska-Syn M M Syn W K WK Xie G G Krüger L L Machado M V MV Karaca G G Michelotti G A GA Choi S S SS Premont R T RT Diehl A M AM

Gut 20131030 8

<h4>Objective</h4>Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH).<h4>Design</h4>αSMA-Cre-ER(T2)×SMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24-96 h post-PH. Regenerating livers were analysed for proliferation, progenitors ...[more]

PMID: 24173292

Similar Datasets

Project description:Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, to explore the molecular mechanisms underlying the tumor-promoting effect of PHx, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had major chromosomal aberrations: all were amplifications affecting multiple chromosomes. Most of these amplifications were located near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. The human orthologs of these common amplified regions are known to be amplified in HCC. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Amplifications in spontaneous tumors affected fewer chromosomes and were not located preferentially at the chromosomal edges. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we revealed that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Our results demonstrate that PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC.

Dataset Information

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.

Publications

Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets