Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation

Valdez, Ivan A.; Dirice, Ercument; Gupta, Manoj Kumar; Shirakawa, Jun; Teo, Adrian Kee Keong

doi:10.1016/j.celrep.2016.03.036

Cited by 62 publications

(60 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, recent studies have demonstrated a critical role for Stat3 in pancreatic cell homeostasis (46,47). Here, early activation of Stat3 overcomes FoxO1 suppression, leading to β-cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

et al. 2017

View full text Add to dashboard Cite

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 β-cell dedifferentiation, followed by a time-dependent decrease in functional β-cell mass—all specifically in the ligated tail portion of the pancreas (PDL-tail). High levels of transforming growth factor β1 (TGFβ1) 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 β-cell mass was then found to result from TGFβ1-triggered epithelial-mesenchymal transition (EMT) by β-cells, rather than resulting directly from β-cell apoptosis. Mechanistically, TGFβ1-treated β-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 β-cells ameliorated β-cell EMT and β-cell loss and prevented the onset of diabetes in mice undergoing PDL. Together, our data suggest that chronic pancreatitis may trigger TGFβ1-mediated β-cell EMT to lead to CPRD, which could substantially be prevented by sustained expression of FoxO1 in β-cells.

show abstract

Section: Discussionmentioning

confidence: 99%

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…At the mature stage, infiltrated macrophage cells were observed frequently in the islet of Tg mice [53]. Chemokine/cytokine-induced epithelial-mesenchymal transition (EMT) in the process of β -cell neogenesis from ductal cells was proposed recently [70]. A similar induction mechanism to that of EMT is likely to be involved, at least partially, in generating new β -cells from duct-like structures, in which the secreted cytokines and chemokines play relevant roles in Tg mice because of SASP-like characters of β -cells [52] and by recruited macrophage cells to the islet [53].…”

Section: Unusual Ductal Structures In the Pancreasmentioning

confidence: 99%

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Okano

2016

Journal of Diabetes Research

View full text Add to dashboard Cite

Cryptochrome proteins (CRYs), which can bind noncovalently to cofactor (chromophore) flavin adenine dinucleotide (FAD), occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice), ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1) being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY). The lowered proliferation of β-cells is a primary cause of age-dependent β-cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β-cells in the Tg mice. This review, based mainly on the author's investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β-cell dysfunction, and regeneration.

show abstract

“…Islet regeneration depends on protein kinase A/signal transducer and activator of transcription 3 (PKA/STAT3) signaling‐mediated NGN3 activation . WB analysis on the retrieved pancreases, at short‐ and long‐term post‐TX, detected STAT3 protein, although in our experimental system we have not confirmed the presence of pSTAT3(TYR705) (data not shown).…”

Section: Resultsmentioning

confidence: 61%

Remission of hyperglycemia in spontaneously diabetic NOD mice upon transplant of microencapsulated human umbilical cord Wharton jelly‐derived mesenchymal stem cells (hUCMS)

Montanucci

Pescara

Alunno

et al. 2018

Xenotransplantation

View full text Add to dashboard Cite

Background: Our previous in vitro demonstration of the immunoregulatory effects of microencapsulated hUCMS on human peripheral blood mononuclear cells (PBMCs) extracted from patients with recent onset, type 1 diabetes mellitus (DM), prompted us to test our product for xenograft (TX) in non obese diabetic (NOD) mice with spontaneous DM. Methods:We transplanted microencapsulated hUCMS into the peritoneal cavity of NOD mice with either severe or mild DM. Blood glucose (BG) levels were monitored following TX, in either basal or upon glucose stimulation. Results:Only the NODs with mild DM showed full and sustained remission of hyperglycemia throughout 216 days post-TX, unlike recipients with severe DM, where no remission of hyperglycemia was attained, as reflected by erratic BG levels at all times. Conclusions:These data suggest that the stage of DM disease process in NOD mice, reflecting steady decline of residual b-cell mass, plays a pivotal role in determining the success of this cell therapy approach for treatment of DM. K E Y W O R D Simmunoregulation, microencapsulation, NOD mice, sodium alginate, stem cells, T1D

show abstract

Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation

Cited by 62 publications

References 53 publications

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Remission of hyperglycemia in spontaneously diabetic NOD mice upon transplant of microencapsulated human umbilical cord Wharton jelly‐derived mesenchymal stem cells (hUCMS)

Contact Info

Product

Resources

About