title: Hepatic Prominin-1 expression is associated with biliary fibrosis.
abstract: Intrahepatic biliary fibrosis, as seen with cholestatic liver injuries such as biliary atresia, is mechanistically distinct from fibrosis caused by hepatocyte toxicity. We previously demonstrated the expansion of cells expressing the stem/progenitor cell marker Prominin-1, within regions of developing fibrosis in biliary atresia. Thus, we hypothesized that Prominin-1 expression is biliary fibrosis-specific.
  
  
  
  Gene expression of Prominin-1 was analyzed in adult mice undergoing either cholestatic bile duct ligation or hepatotoxic carbon tetrachloride administration by quantitative polymerase chair reaction. Lineage tracing of Prominin-1-expressing cells and Collagen-1α-expressing cells was performed after bile duct ligation in Prominin-1cre-ert2-lacz;Gfplsland Collagen-1αGfptransgenic mice, respectively.
  
  
  
  Prominin-1 expression increased significantly after bile duct ligation compared with sham (6.6 ± 0.9-fold change at 2 weeks, P < .05) but not with carbon tetrachloride (-0.7 ± 0.5-fold change, not significant). Upregulation of Prominin-1 was observed histologically throughout the liver as early as 5 days after bile duct ligation in Prominin-1cre-ert2-laczmice by LacZ staining in nonhepatocyte cells. Lineage tracing of Prominin-1-expressing cells labeled prior to bile duct ligation in Prominin-1cre-ert2-lacz;Gfplslmice, demonstrated increasing colocalization of GREEN FLUORESCENT PROTEIN with biliary marker CYTOKERATIN-19 within ductular reactions up to 5 weeks after bile duct ligation consistent with biliary transdifferentiation. In contrast, rare colocalization of GREEN FLUORESCENT PROTEIN with mesenchymal marker α-SMOOTH MUSCLE ACTIN in Prominin-1cre-ert2-lacz;Gfplslmice and some colocalization of GREEN FLUORESCENT PROTEIN with PROMININ-1 in Collagen-1αGfpmice, indicate minimal contribution of Prominin-1 progenitor cells to the pool of collagen-producing myofibroblasts.
  
  
  
  During biliary fibrosis Prominin-1-expressing progenitor cells transdifferentiate into cells within ductular reactions. This transdifferentiation may promote fibrosis.
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Marie V
authors.initials: MV
authors.lastname: Nguyen
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Zagory
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: William H
authors.initials: WH
authors.lastname: Dietz
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Alex
authors.initials: A
authors.lastname: Park
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fenlon
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Menghan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Jiabo
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lua
authors.affiliation: Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Mavila
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Kinji
authors.initials: K
authors.lastname: Asahina
authors.affiliation: Division of Pediatric Surgery, Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA. Electronic address: kwang@chla.usc.edu.
authors.forename: Kasper S
authors.initials: KS
authors.lastname: Wang
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000473:pathology*; D002779:Cholestasis / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D012333:RNA, Messenger