TY - JOUR T1 - Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy JF - Gut JO - Gut SP - 1333 LP - 1344 DO - 10.1136/gutjnl-2013-305962 VL - 63 IS - 8 AU - M Swiderska-Syn AU - W K Syn AU - G Xie AU - L Krüger AU - M V Machado AU - G Karaca AU - G A Michelotti AU - S S Choi AU - R T Premont AU - A M Diehl Y1 - 2014/08/01 UR - http://gut.bmj.com/content/63/8/1333.abstract N2 - 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. ER -