Inactivation of TGFβ receptor II signalling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis.
Determining signalling pathways that regulate pancreatic regeneration following pancreatitis is critical for implementing therapeutic interventions. In this study we elucidated the molecular mechanisms underlying the effects of transforming growth factor-β (TGFβ) in pancreatic epithelial cells during tissue regeneration. To this end, we conditionally inactivated TGFβ receptor II (TGFβ-RII) using a Cre-LoxP system under the control of pancreas transcription factor 1a (PTF1a) promoter, specific for the pancreatic epithelium, and evaluated the molecular and cellular changes in a mouse model of cerulein-induced pancreatitis. We show that TGFβ-RII signalling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGFβ-RII signalling not only restricts acinar cell replication during the regenerative phase of the disease but also limits ADM formation in vivo and in vitro in a cell-autonomous manner. Analyses of molecular mechanisms underlying the observed phenotype revealed that TGFβ-RII signalling stimulates the expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signalling axis. Finally, TGFβ-RII ablation in epithelial cells resulted in increased infiltration of inflammatory cells in the early phases of pancreatitis and increased activation of pancreatic stellate cells in the later stages of pancreatitis, thus highlighting a TGFβ-based crosstalk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarifying the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGFβ as a tumour suppressor, both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer.
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Kamile
K
Grabliauskaite
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Enrica
E
Saponara
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Theresia
T
Reding
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Marta
M
Bombardo
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Gitta M
GM
Seleznik
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Ermanno
E
Malagola
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Anja
A
Zabel
Institute of Parasitology, University of Zurich, Switzerland.
Carmen
C
Faso
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Sabrina
S
Sonda
Swiss Hepato-Pancreato-Biliary Centre, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, and Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Rolf
R
Graf
D061354:Acinar Cells / Q000473:pathology*; D000681:Amylases / Q000378:metabolism; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D004847:Epithelial Cells / Q000473:pathology; D005355:Fibrosis / Q000473:pathology; D007509:Irritants / Q000633:toxicity; D008049:Lipase / Q000378:metabolism; D008297:Male; D008679:Metaplasia / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000201:enzymology / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology; D010195:Pancreatitis / Q000201:enzymology / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D007509:Irritants; D018125:Receptors, Transforming Growth Factor beta; D002108:Ceruletide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D008049:Lipase; D000681:Amylases
TGFβ signalling; fibrosis; pancreatitis; regeneration