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Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy
  1. M Swiderska-Syn1,
  2. W K Syn1,2,
  3. G Xie1,
  4. L Krüger1,
  5. M V Machado1,
  6. G Karaca1,
  7. G A Michelotti1,
  8. S S Choi1,3,
  9. R T Premont1,
  10. A M Diehl1
  1. 1Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
  2. 2Department of Regeneration and Repair, Institute of Hepatology, Foundation for Liver Research, London, UK
  3. 3Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA
  1. Correspondence to Professor Anna Mae Diehl, Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 595 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC 27710, USA; diehl004{at}mc.duke.edu

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-ERT2×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-ERT2×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.

  • LIVER REGENERATION
  • BASIC SCIENCES
  • MOLECULAR MECHANISMS

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