title: Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets.
abstract: Multipotent stem/progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato-pancreatic common duct, cystic duct, and hilum. They express endodermal transcription factors (e.g., Sox9, SOX17, FOXA2, PDX1, HES1, NGN3, PROX1) intranuclearly, stem/progenitor surface markers (EpCAM, NCAM, CD133, CXCR4), and sometimes weakly adult liver, bile duct, and pancreatic genes (albumin, cystic fibrosis transmembrane conductance regulator [CFTR], and insulin). They clonogenically expand on plastic and in serum-free medium, tailored for endodermal progenitors, remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈36 hours and slowing to one every 2-3 days. Transfer into distinct culture conditions, each comprised of a specific mix of hormones and matrix components, yields either cords of hepatocytes (express albumin, CYP3A4, and transferrin), branching ducts of cholangiocytes (expressing anion exchanger-2-AE2 and CFTR), or regulatable C-peptide secreting neoislet-like clusters (expressing glucagon, insulin) and accompanied by changes in gene expression correlating with the adult fate. Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes, whereas if into fat pads of streptozocin-induced diabetic mice, results in functional islets secreting glucose-regulatable human C-peptide.
  
  
  CONCLUSIONS
  The phenotypes and availability from all age donors suggest that these stem/progenitors have considerable potential for regenerative therapies of liver, bile duct, and pancreatic diseases including diabetes.
authors.affiliation: Department of Cell and Molecular Physiology, Biomedical Engineering, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cardinale
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Wang
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Cai-Bin
authors.initials: CB
authors.lastname: Cui
authors.forename: Manuela
authors.initials: M
authors.lastname: Gatto
authors.forename: Massimo
authors.initials: M
authors.lastname: Rossi
authors.forename: Pasquale Bartolomeo
authors.initials: PB
authors.lastname: Berloco
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cantafora
authors.forename: Eliane
authors.initials: E
authors.lastname: Wauthier
authors.forename: Mark E
authors.initials: ME
authors.lastname: Furth
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
authors.forename: Juan
authors.initials: J
authors.lastname: Dominguez-Bendala
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: David
authors.initials: D
authors.lastname: Gerber
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Lola
authors.initials: L
authors.lastname: Reid
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology*; D012038:Regeneration / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis; D014183:Transplantation, Heterologous
chemical_list: D014157:Transcription Factors