title: Notch signaling as gatekeeper of rat acinar-to-beta-cell conversion in vitro.
abstract: OBJECTIVE
  Exocrine acinar cells in the pancreas are highly differentiated cells that retain a remarkable degree of plasticity. After isolation and an initial phase of dedifferentiation in vitro, rodent acinar cells can convert to endocrine beta-cells when cultured in the presence of appropriate factors. The mechanisms regulating this phenotypic conversion are largely unknown.
  
  
  METHODS
  Using rat acinar cell cultures, we studied the role of Notch signaling in a model of acinar-to-beta-cell conversion.
  
  
  RESULTS
  We report a novel lectin-based cell labeling method to demonstrate the acinar origin of newly formed insulin-expressing beta-cells. This method allows for specific tracing of the acinar cells. We demonstrate that growth factor-induced conversion of adult acinar cells to beta-cells is negatively regulated by Notch1 signaling. Activated Notch1 signaling prevents the reexpression of the proendocrine transcription factor Neurogenin-3, the key regulator of endocrine development in the embryonic pancreas. Interfering with Notch1 signaling allows modulating the acinar cell susceptibility to the differentiation-inducing factors. Its inhibition significantly improves beta-cell neoformation with approximately 30% of acinar cells that convert to beta-cells. The newly formed beta-cells mature when transplanted ectopically and are capable of restoring normal blood glycemia in diabetic recipients.
  
  
  CONCLUSIONS
  We report for the first time an efficient way to reprogram one third of the acinar cells to beta-cells by adult cell type conversion. This could find application in cell replacement therapy of type 1 diabetes, provided that it can be translated from rodent to human models.
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Baeyens
authors.forename: Stefan
authors.initials: S
authors.lastname: Bonné
authors.forename: Tomas
authors.initials: T
authors.lastname: Bos
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.forename: Cindy
authors.initials: C
authors.lastname: Peleman
authors.forename: Tony
authors.initials: T
authors.lastname: Lahoutte
authors.forename: Michael
authors.initials: M
authors.lastname: German
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Luc
authors.initials: L
authors.lastname: Bouwens
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D051881:Receptor, Notch1