Notch signaling is required for exocrine regeneration after acute pancreatitis.
OBJECTIVE
The mechanisms for tissue regeneration and renewal after acute pancreatitis are not well understood but may involve activation of Notch signaling. To study the effect of Notch signaling ablation during acute experimental pancreatitis, we used a chemical and genetic approach to ablate Notch signaling in cerulein-induced pancreatitis in mice.


METHODS
Acute pancreatitis was induced by cerulein treatment in mice treated with the gamma-secretase inhibitor dibenzazepine or in conditional Notch1 knockout mice. Mice were characterized using immunohistologic, biochemical, and molecular methods. To investigate Notch and beta-catenin interaction, acinar 266-6 cells were analyzed using transfection and biochemical assays.


RESULTS
Loss of Notch signaling results in impaired regeneration after acute pancreatitis with fewer mature acinar cells in dibenzazepine-treated and Notch1-deficient mice in the regenerative phase 3 days after induction. beta-catenin expression was increased and prolonged during exocrine regeneration. Crosstalk between Notch and beta-catenin-mediated signaling was identified, with Notch1-IC inhibiting beta-catenin-mediated transcriptional activity. This inhibition was dependent on a functional RAM domain.


CONCLUSIONS
Inhibition of Notch signaling in vivo leads to impaired regeneration of the exocrine pancreas after acute pancreatitis. Our results suggest an interaction of Notch and Wnt signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells.
Siveke
Jens T
JT
Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, München, Germany.
Lubeseder-Martellato
Clara
C
Lee
Marcel
M
Mazur
Pawel K
PK
Nakhai
Hassan
H
Radtke
Freddy
F
Schmid
Roland M
RM
D000208:Acute Disease; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D045744:Cell Line, Tumor; D002108:Ceruletide; D003984:Dibenzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000473:pathology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D003984:Dibenzazepines; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051153:Wnt Proteins; D051176:beta Catenin; D002108:Ceruletide; D053829:Amyloid Precursor Protein Secretases