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Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis
  1. Andreia V Pinho1,2,*,
  2. Ilse Rooman2,3,*,
  3. Maximilian Reichert4,
  4. Nele De Medts3,
  5. Luc Bouwens3,
  6. Anil K Rustgi4,
  7. Francisco X Real1,2,5
  1. 1Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
  2. 2Institut Municipal d'Investigació Mèdica-Hospital del Mar, Barcelona, Spain
  3. 3Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
  4. 4Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA
  5. 5Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  1. Correspondence to Dr Francisco X Real, Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029-Madrid, Spain; preal{at}cnio.es

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.

Design 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.

  • Acinar cells
  • pancreatic progenitors
  • dedifferentiation
  • senescence
  • chronic pancreatitis
  • pancreatic ductal adenocarcinoma
  • pancreatic cancer
  • pancreatic damage
  • pancreatic enzymes
  • pancreatitis
  • stem cells

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Footnotes

  • * AVP and IR made equivalent contributions and share first authorship.

  • Funding This work was supported, in part, by grant SAF2007-60860 and ONCOBIO Consolider from Ministerio de Ciencia e Innovación (Madrid, Spain) to FXR; grant EU-Marie Curie-ERG 204582 to IR; grant FWO G 0480 06 N to LB. AVP was supported by grant SFRH/BD/15902/2005 from Foundation for Science and Technology (FCT), Portugal and is a fellow of the Graduate Program in Areas of Basic and Applied Biology (GABBA), University of Porto, Portugal. IR was supported, in part, by the Fund for Scientific Research Flanders (FWO) and by the Francqui Foundation. There was also support from NIH RO1 DK060694 (AKR, MR) and National Pancreas Foundation (MR).

  • Competing interests None.

  • Ethics approval All mouse experiments were performed in accordance with institutional ethics committees and national guidelines and regulations.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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