title: Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis.
abstract: OBJECTIVE
  Acinar cells display plasticity in vitro and in vivo and can activate a variety of differentiation programmes that may contribute to pancreatic diseases. The aims were to determine: (1) the differentiation potential of acinar cells under conditions which favour stem cell survival, and (2) its relationship to the phenotypes acquired by pancreatic epithelial cells in chronic pancreatitis.
  
  
  METHODS
  Murine acinar cells were cultured in suspension and their molecular phenotype was characterised by qRT-PCR, chromatin immunoprecipitation, immunocytochemistry and global transcriptome analysis. These findings were compared to the changes occurring in experimental chronic pancreatitis induced by pancreatic duct ligation and chronic caerulein administration.
  
  
  RESULTS
  Acinar cells in suspension culture acquired a dedifferentiated phenotype characteristic of pancreatic embryonic progenitors, consisting of the co-expression of Ptf1a and Pdx1, presence of an embryonic-type PTF1 transcriptional complex, activation of the Notch pathway, and expression of additional pancreatic progenitor cell markers such as CpA1, Sox9 and Hnf1b. A senescence programme, associated with activation of Ras and ERK signalling, limited the proliferative capacity of the cells. A similar progenitor-like phenotype with activation of a senescence programme was observed in experimental chronic pancreatitis induced by pancreatic duct ligation or repeated caerulein administration, with the concomitant and differential activation of proliferation and senescence in distinct cell populations.
  
  
  CONCLUSIONS
  Acinar cells dedifferentiate into an embryonic progenitor-like phenotype upon suspension culture. This is associated with the activation of a senescence programme. Both processes take place in experimental chronic pancreatitis where senescence may contribute to limit tumour progression.
authors.affiliation: Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029-Madrid, Spain.
authors.forename: Andreia V
authors.initials: AV
authors.lastname: Pinho
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.forename: Nele
authors.initials: N
authors.lastname: De Medts
authors.forename: Luc
authors.initials: L
authors.lastname: Bouwens
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002108:Ceruletide; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000473:pathology*; D020869:Gene Expression Profiling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D046790:Pancreas, Exocrine / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000473:pathology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002108:Ceruletide