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Inactivation of TGF-β receptor II signaling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis


Grabliauskaite, Kamile; Saponara, Enrica; Reding, Theresia; Bombardo, Marta; Seleznik, Gitta M; Malagola, Ermanno; Zabel, Anja; Faso, Carmen; Sonda, Sabrina; Graf, Rolf (2016). Inactivation of TGF-β receptor II signaling in pancreatic epithelial cells promotes acinar cell proliferation, acinar-to-ductal metaplasia and fibrosis during pancreatitis. Journal of Pathology, 238(3):434-445.

Abstract

Determining signaling 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 (TGF-β) in pancreatic epithelial cells during tissue regeneration. To this aim, we conditionally inactivated TGF-β receptor II (TGF-β 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 TGF-β RII signaling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGF-β RII signaling 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 TGF-β RII signaling stimulates expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signaling axis. Finally, TGF-β 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 TGF-β-based cross-talk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarify the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGF-β as a tumor suppressor both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer.

Abstract

Determining signaling 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 (TGF-β) in pancreatic epithelial cells during tissue regeneration. To this aim, we conditionally inactivated TGF-β receptor II (TGF-β 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 TGF-β RII signaling does not mediate the initial acinar cell damage observed at the onset of pancreatitis. However, TGF-β RII signaling 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 TGF-β RII signaling stimulates expression of cyclin-dependent kinase inhibitors and intersects with the EGFR signaling axis. Finally, TGF-β 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 TGF-β-based cross-talk between epithelial and stromal cells regulating the development of pancreatic inflammation and fibrosis. Collectively, our data not only contribute to clarify the cellular processes governing pancreatic tissue regeneration, but also emphasize the conserved role of TGF-β as a tumor suppressor both in the regenerative process following pancreatitis and in the initial phases of pancreatic cancer.

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1 citation in Web of Science®
1 citation in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2016
Deposited On:26 Jan 2016 11:35
Last Modified:27 Apr 2016 13:33
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0022-3417
Publisher DOI:https://doi.org/10.1002/path.4666
PubMed ID:26510396

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