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Gut. 2014 Aug;63(8):1333-44. doi: 10.1136/gutjnl-2013-305962. Epub 2013 Oct 30.

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

Author information

1
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
2
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Department of Regeneration and Repair, Institute of Hepatology, Foundation for Liver Research, London, UK.
3
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.

Abstract

OBJECTIVE:

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).

DESIGN:

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 and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, αSMA-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).

RESULTS:

Post-PH, VEH-αSMA-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-αSMA-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-αSMA-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 αSMA-YFP+ cells.

CONCLUSIONS:

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.

KEYWORDS:

BASIC SCIENCES; LIVER REGENERATION; MOLECULAR MECHANISMS

PMID:
24173292
PMCID:
PMC4006344
DOI:
10.1136/gutjnl-2013-305962
[Indexed for MEDLINE]
Free PMC Article

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