Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Abstract

Pancreatic duct cells are considered a potential source of β-cell regeneration, and transforming growth factor-β (TGF-β) has been suggested to perform an important role in these processes, but the underlying mechanism of the signal pathways, especially in humans, remains poorly understood. To evaluate the role of TGF-β1, pancreatic duct cells were isolated from three brain-dead organ donors. Pancreatic cell clusters harvested after islet isolation were dispersed to single cells and cultured in monolayers, then treated with TGF-β1. We analyzed the characteristics of the cultured cells, the TGF-β1 intracellular signaling pathway, the proliferation, and transdifferentiation rates of the duct cells. We also evaluated the genes and protein expression patterns after TGF-β1 treatment. After TGF-β1 treatment, typical morphologic changes representative of EMT were observed and Erk1/2, JNK, and AKT phosphorylation, Ras downstream effectors, were increased. β cell-specific transcription factors including PDX-1, Beta2/NeuroD, Ist-1, and NGN3 were markedly suppressed and the rate of transdifferentiation into β cells was also suppressed. Genomic and proteomic analyses suggested that TGF-β1 induces marked changes in a variety of structural genes and proteins associated with EMT. In conclusion, TGF-β1 induces EMT in cultured human pancreatic duct cells, but suppresses its proliferation and transdifferentiation into β cells. Our results are the first report of TGF-β1 effects for EMT and ductal cell transdifferentiation and proliferation at the protein level in human pancreatic duct cells.

A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension

“…The use of a similar pan-TGF-b neutralizing antibody in humans, fresolimumab, although generally well-tolerated, has been associated with dose-related side effects, including skin rashes and lesions, epistaxis, gingival bleeding, and fatigue (36). Moreover, TGF-b2 is essential in cardiac valve morphogenesis, which is consistent with its central role in regulating endothelial-and epithelial-tomesenchymal transition in a variety of tissues (20)(21)(22)(23)(24)(25)(26)(27)(28), and raising the possibility that its inhibition might contribute to the valvular toxicity seen with small molecule inhibitors of ALK4/5/7. Consistent with the concept that the TGF-b type II receptor does not transduce TGF-b2 signals in the absence of the type III co-receptor betaglycan (19,(45)(46)(47), soluble TGFBRII-Fc did not inhibit TGF-b2 or cause any observable changes in cardiac valve structure or function.…”

“…We propose that this ligand trap strategy might ameliorate several aspects of pulmonary vascular remodeling and PH that are specifically caused by the activities of TGF-b1 and TGF-b3, without incurring the toxic liabilities due to the inhibition of TGF-b2. TGF-b2 is known to be unique among TGF-b ligands for its essential roles in cardiac valve morphogenesis, and regulating endothelial and epithelial-tomesenchymal transition in a variety of tissues (20)(21)(22)(23)(24)(25)(26)(27)(28). Part of the present study has been previously reported in abstract form (29).…”

TCF7L2 promotes beta cell regeneration in human and mouse pancreas

“…Growth factors such as epidermal growth factor in combination with gastrin [38], IGF, TGF-beta [22,39] and the acinar cell product known as islet neogenesis-associated protein [40] foster beta cell growth. The activation of the JAK2/STAT3 pathway occurs during generation of beta cells [22].…”

Ginsenoside Rg1 attenuates invasion and migration by inhibiting transforming growth factor-β1-induced epithelial to mesenchymal transition in HepG2 cells

“…These cells then acquire a highly motile fibroblastoid or mesenchymal phenotype (22,23). TGF-β1 is major inducer of EMT and several studies have demonstrated that TGF-β1 alone or in combination with other growth factors, including EGF and hepatocyte growth factor is critical in mediating EMT in various types of malignant tumor (24,25). Consistent with these studies, the present study found that TGF-β1 induces HepG2 cells to undergo EMT and the cells acquire a spindle-like fibroblastic phenotype and reduce their cell-cell contact.…”