title: Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor.
abstract: Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) the reversible differentiation fate of HepaRG cells is related to the absence of p21(CIP1) and p53 accumulation in differentiated cells; (2) HepaRG bipotent progenitors express the main markers of in vivo hepatic progenitors, and that cell differentiation process is linked to loss of their expression; (3) early and transient changes of beta-catenin localization and HNF3beta expression are correlated to Notch3 upregulation during hepatobiliary commitment of HepaRG cells.
  
  
  CONCLUSIONS
  Our results demonstrate the great plasticity of transformed hepatic progenitor cells and suggest that the transdifferentiation process could supply the pool of hepatic progenitor cells. Moreover, they highlight possible mechanisms by which transdifferentiation and proliferation of unipotent hepatocytes might cooperate in the development of mixed and differentiated tumors.
authors: Inserm, U522, CHU Pontchaillou, F-35033 Rennes, France.
authors: Virginie
authors: V
authors: Cerec
authors: Denise
authors: D
authors: Glaise
authors: Delphine
authors: D
authors: Garnier
authors: Serban
authors: S
authors: Morosan
authors: Bruno
authors: B
authors: Turlin
authors: Bernard
authors: B
authors: Drenou
authors: Philippe
authors: P
authors: Gripon
authors: Dina
authors: D
authors: Kremsdorf
authors: Christiane
authors: C
authors: Guguen-Guillouzo
authors: Anne
authors: A
authors: Corlu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D017690:Cell Transplantation; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000502:physiology*
chemical_list: D015415:Biomarkers