title: Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis.
abstract: Whether or not cholangiocytes or their hepatic progenitors undergo an epithelial-to-mesenchymal transition (EMT) to become matrix-producing myofibroblasts during biliary fibrosis is a significant ongoing controversy. To assess whether EMT is active during biliary fibrosis, we used Alfp-Cre × Rosa26-YFP mice, in which the epithelial cells of the liver (hepatocytes, cholangiocytes, and their bipotential progenitors) are heritably labeled at high efficiency with yellow fluorescent protein (YFP). Primary cholangiocytes isolated from our reporter strain were able to undergo EMT in vitro when treated with transforming growth factor-β1 alone or in combination with tumor necrosis factor-α, as indicated by adoption of fibroblastoid morphology, intracellular relocalization of E-cadherin, and expression of α-smooth muscle actin (α-SMA). To determine whether EMT occurs in vivo, we induced liver fibrosis in Alfp-Cre × Rosa26-YFP mice using the bile duct ligation (BDL) (2, 4, and 8 weeks), carbon tetrachloride (CCl(4) ) (3 weeks), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 2 and 3 weeks) models. In no case did we find evidence of colocalization of YFP with the mesenchymal markers S100A4, vimentin, α-SMA, or procollagen 1α2, although these proteins were abundant in the peribiliary regions.
  
  
  CONCLUSIONS
  Hepatocytes and cholangiocytes do not undergo EMT in murine models of hepatic fibrosis.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chu
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Diaz
authors.forename: Jia-Ji
authors.initials: JJ
authors.lastname: Hui
authors.forename: Kilangsungla
authors.initials: K
authors.lastname: Yanger
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zong
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Wells
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology*; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice