title: Lack of evidence that bone marrow cells contribute to cholangiocyte repopulation during experimental cholestatic ductal hyperplasia.
abstract: BACKGROUND
  Ductopenia is observed in end-stage human cholestatic diseases. The limited capability of cholangiocytes for proliferation is suggested to be the principal reason. Recently, bone marrow cells (BMCs) have been reported to behave as hepatic stem cells; however, their capability to differentiate into cholangiocytes in cholestasis remains unclear.
  
  
  METHODS
  Normal mice were lethally irradiated to suppress the proliferation of self-BMCs; thereafter, the BMCs from enhanced green fluorescent protein (EGFP)-transgenic mice were transferred to recipients. Chronic cholestasis was induced by 0.1%alpha-naphtylisothiocyanate (ANIT) feeding. The proliferation of cholangiocytes and oval cells was assessed morphologically and immunohistchemically (cytokeratin-7 (CK-7), A6). Proliferative activity (proliferating cell nuclear antigen (PCNA) protein expression), hepatic growth factor (HGF) receptor (c-Met), stem cell factor receptor (c-kit), Notch2 and Hes1 expression were also evaluated.
  
  
  RESULTS
  Marked cholangiocyte proliferation was observed in ANIT-fed mice. However, no EGFP/CK-7 double positive cells were identified in any of the liver specimens after BMCs transfer (Tx). In hepatic parenchyma, there were scattered EGFP-positive cells, although none of them were positive for CK-7.
  
  
  CONCLUSIONS
  In spite of the significant ductular proliferations after ANIT feeding, no EGFP-positive cholangiocytes were confirmed by any other means in this chronic cholestasis model. Thus, different from hepatocytes, BMCs Tx seems not to contribute to the differentiation of cholangiocytes. Future studies are feasible to clarify the origin of proliferative cholangiocytes observed in this chronic cholestatic ductular hyperplasia model.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai Miyagi, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Noriatsu
authors.initials: N
authors.lastname: Kanno
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamagiwa
authors.forename: Koji
authors.initials: K
authors.lastname: Fukushima
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D015058:1-Naphthylisothiocyanate; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001652:Bile Ducts / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006965:Hyperplasia / Q000473:pathology; D053552:Keratin-7; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D000072056:Transcription Factor HES-1
chemical_list: D015058:1-Naphthylisothiocyanate; D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D053552:Keratin-7; D007633:Keratins; D008840:Microfilament Proteins; D011505:Protein-Tyrosine Kinases; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C507497:KRT7 protein, human; C507496:Krt7 protein, mouse; C485184:enhanced green fluorescent protein; C485190:Twf1 protein, mouse