title: Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.
abstract: Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. Whereas the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a rhesus rotavirus-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker, PROMININ-1 (PROM1), adjacent to ductular reactions within regions of periportal fibrosis. PROM1positive (pos) cells express Collagen-1α1. Subsets of PROM1pos cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (αSMA). Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGFβ) signaling. In vitro cotreatment of PROM1-expressing Mat1a-/- hepatic progenitor cells with recombinant human FGF10 and TGFβ1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1α1, Fibronectin, and α-Sma. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated Mothers Against Decapentaplegic Homolog 3 (SMAD3) signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype.
  
  
  CONCLUSIONS
  Expansion of collagen-producing PROM1pos cells within regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1pos cells may therefore play an important role in the biliary fibrosis of BA.
authors.affiliation: Developmental Biology, Regenerative Medicine and Stem Cell Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Mavila
authors.forename: David
authors.initials: D
authors.lastname: James
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.forename: Marie V
authors.initials: MV
authors.lastname: Nguyen
authors.forename: Sarah
authors.initials: S
authors.lastname: Utley
authors.forename: Katrina
authors.initials: K
authors.lastname: Mak
authors.forename: Allison
authors.initials: A
authors.lastname: Wu
authors.forename: Shengmei
authors.initials: S
authors.lastname: Zhou
authors.forename: Larry
authors.initials: L
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Vendyres
authors.forename: Megan
authors.initials: M
authors.lastname: Groff
authors.forename: Kinji
authors.initials: K
authors.lastname: Asahina
authors.forename: Kasper S
authors.initials: KS
authors.lastname: Wang
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001656:Biliary Atresia / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012400:Rotavirus Infections / Q000150:complications; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt