title: Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.
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).
  
  
  METHODS
  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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: 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.
authors.forename: W K
authors.initials: WK
authors.lastname: Syn
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: L
authors.initials: L
authors.lastname: Krüger
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: G
authors.initials: G
authors.lastname: Karaca
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: 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.
authors.forename: S S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D005355:Fibrosis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics; D006498:Hepatectomy; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000199:Actins; D018931:Antineoplastic Agents, Hormonal; D053823:Hedgehog Proteins; D008164:Luminescent Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C544013:alpha-smooth muscle actin, mouse; D013629:Tamoxifen
keywords: BASIC SCIENCES; LIVER REGENERATION; MOLECULAR MECHANISMS