Dataset Information


SMAD3/Stat3 Signaling Mediates ?-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis-Related Diabetes.

ABSTRACT: Many patients with chronic pancreatitis develop diabetes (chronic pancreatitis-related diabetes [CPRD]) through an undetermined mechanism. Here we used long-term partial pancreatic duct ligation (PDL) as a model to study CPRD. We found that long-term PDL induced significant ?-cell dedifferentiation, followed by a time-dependent decrease in functional ?-cell mass-all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor ?1 (TGF?1) were detected in the PDL-tail and were mainly produced by M2 macrophages at the early stage and by activated myofibroblasts at the later stage. Loss of ?-cell mass was then found to result from TGF?1-triggered epithelial-mesenchymal transition (EMT) by ?-cells, rather than resulting directly from ?-cell apoptosis. Mechanistically, TGF?1-treated ?-cells activated expression of the EMT regulator gene Snail in a SMAD3/Stat3-dependent manner. Moreover, forced expression of forkhead box protein O1 (FoxO1), an antagonist for activated Stat3, specifically in ?-cells ameliorated ?-cell EMT and ?-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGF?1-mediated ?-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in ?-cells.


PROVIDER: S-EPMC5606322 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

2019-01-01 | S-EPMC6787444 | BioStudies
2015-01-01 | S-EPMC4587799 | BioStudies
2019-01-01 | S-EPMC6848388 | BioStudies
2010-01-01 | S-EPMC3034255 | BioStudies
1000-01-01 | S-EPMC4274809 | BioStudies
2016-01-01 | S-EPMC5143397 | BioStudies
1000-01-01 | S-EPMC3974079 | BioStudies
2020-01-01 | S-EPMC7403491 | BioStudies
2012-01-01 | S-EPMC3337240 | BioStudies
1000-01-01 | S-EPMC3432854 | BioStudies