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

Publication ,  Journal Article
Swiderska-Syn, M; Syn, WK; Xie, G; Krüger, L; Machado, MV; Karaca, G; Michelotti, GA; Choi, SS; Premont, RT; Diehl, AM
Published in: Gut
August 2014

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.

Duke Scholars

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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

August 2014

Volume

63

Issue

8

Start / End Page

1333 / 1344

Location

England

Related Subject Headings

  • Tamoxifen
  • Stem Cells
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Myofibroblasts
  • Mice
  • Luminescent Proteins
  • Liver Regeneration
  • Immunohistochemistry
 

Citation

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Chicago
ICMJE
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Swiderska-Syn, M., Syn, W. K., Xie, G., Krüger, L., Machado, M. V., Karaca, G., … Diehl, A. M. (2014). Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut, 63(8), 1333–1344. https://doi.org/10.1136/gutjnl-2013-305962
Swiderska-Syn, M., W. K. Syn, G. Xie, L. Krüger, M. V. Machado, G. Karaca, G. A. Michelotti, S. S. Choi, R. T. Premont, and A. M. Diehl. “Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.Gut 63, no. 8 (August 2014): 1333–44. https://doi.org/10.1136/gutjnl-2013-305962.
Swiderska-Syn M, Syn WK, Xie G, Krüger L, Machado MV, Karaca G, et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut. 2014 Aug;63(8):1333–44.
Swiderska-Syn, M., et al. “Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy.Gut, vol. 63, no. 8, Aug. 2014, pp. 1333–44. Pubmed, doi:10.1136/gutjnl-2013-305962.
Swiderska-Syn M, Syn WK, Xie G, Krüger L, Machado MV, Karaca G, Michelotti GA, Choi SS, Premont RT, Diehl AM. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut. 2014 Aug;63(8):1333–1344.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

August 2014

Volume

63

Issue

8

Start / End Page

1333 / 1344

Location

England

Related Subject Headings

  • Tamoxifen
  • Stem Cells
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Myofibroblasts
  • Mice
  • Luminescent Proteins
  • Liver Regeneration
  • Immunohistochemistry