Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors

Brown, Melissa; Ungerleider, Nathan; Bonomi, Lara; Andrzejewski, Danielle; Burnside, Amy; Schneyer, Alan L.

doi:10.1080/19382014.2015.1017226

Cited by 13 publications

(14 citation statements)

References 39 publications

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“…In addition, harmine treatment of human islets resulted in notable changes in TGFbSF members (Tables S1 and S2). Reasoning from these observations, from the prominence of SMAD signaling in human insulinoma cell proliferation , and from the beneficial effects of TGFb signaling inhibition in mouse islets described by Bhushan, Gittes, Kim, Schneyer, and Teramoto et al (Brown and Schneyer, 2010;Brown et al, 2014;Dhawan et al, 2016;El-Gohary et al, 2014;Mukherjee et al, 2007;Nomura et al, 2014;Smart et al, 2006;Xiao et al, 2014Xiao et al, , 2016Zhou et al, 2013), we explored the effects of TGFbSF pharmacologic inhibitors on human beta cell proliferation in a large number of human cadaveric islet preparations . Vehicle alone (DMSO) had no effect, and harmine displayed its usual $2% labeling index , as assessed using Ki67 labeling of insulin-positive cells.…”

Section: Combinations Of Dyrk1a Inhibitors and Tgfbsfmentioning

confidence: 99%

“…R-SMADs may transactivate or repress genes, and may do so in complexes that include Trithorax members (Antebi et al, 2017;Brown and Schneyer, 2010;Brown et al, 2014;Chandrasekharappa et al, 1997;Chen et al, 2009Chen et al, , 2011Crabtree et al, 2001Crabtree et al, , 2003Dhawan et al, 2009Dhawan et al, , 2016El-Gohary et al, 2014;Gaarenstroom and Hill, 2014;Macias et al, 2015;Nomura et al, 2014;Smart et al, 2006;Stewart et al, 2015;Xiao et al, 2014Xiao et al, , 2016Zhou et al, 2013). Both Trithorax and SMAD signaling have been implicated in beta cell proliferation in human insulinoma .…”

Section: Effects Of R-smads and Trithorax Complex On Cell-cycle Inhibmentioning

confidence: 99%

“…Second, as described below, we observed that TGFbSF members were abundant in isolated human beta cells, and some were affected by pharmacologic DYRK1A inhibition. Third, Gittes et al;Teramoto et al,;and Annes et al (Abdolazimi et al, 2018;Brown and Schneyer, 2010;Brown et al, 2014;Dhawan et al, 2016;El-Gohary et al, 2014;Mukherjee et al, 2007;Nomura et al, 2014;Smart et al, 2006;Xiao et al, 2014Xiao et al, , 2016Zhou et al, 2013) have each reported that genetic or pharmacologic TGFbSF pathway inhibition in rodent beta cells can lead to rodent beta cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…Transforming growth factor beta superfamily (TGFbSF) signaling is complex (Antebi et al, 2017;Brown and Schneyer, 2010;Brown et al, 2014;Dhawan et al, 2016;El-Gohary et al, 2014;Gaarenstroom and Hill, 2014;Macias et al, 2015;Mukherjee et al, 2007;Nomura et al, 2014;Smart et al, 2006;Stewart et al, 2015;Xiao et al, 2014Xiao et al, , 2016Zhou et al, 2013). In its simplest form, it involves a series of ligands (e.g., TGFbs 1,2,3, activins, inhibins, glia-derived factors, and bone morphogenic proteins), a series of cognate receptors, and a repertoire of endogenous inhibitors (e.g., sclerostin and follistatin-like factors) that signal downstream through a series of activating or receptor R-SMADs (SMADs 1,2,3,5,8/9) and the co-SMAD, SMAD4, and are blocked by one of two inhibitory I-SMADs (SMADs 6,7).…”

Section: Introductionmentioning

confidence: 99%

“…Once activated, R-SMAD heteromers translocate to the nucleus, where they serve individually or in complexes to transactivate or repress target genes. Notably, at some of these loci, SMADs integrate into epigenetic chromatin-modifying complexes, such as the trithorax group complex (TrxG) that includes histone methylases (e.g., MEN1) and histone demethlyases (e.g., KDM6A) that regulate chromatin access (Antebi et al, 2017;Brown and Schneyer, 2010;Brown et al, 2014;Dhawan et al, 2016;El-Gohary et al, 2014;Gaarenstroom and Hill, 2014;Macias et al, 2015;Mukherjee et al, 2007;Nomura et al, 2014;Smart et al, 2006;Stewart et al, 2015;Xiao et al, 2014Xiao et al, , 2016Zhou et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

Wang¹,

Karaköse²,

Liu³

et al. 2019

Cell Metabolism

123

209

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Highlights d Adult human pancreatic beta cells can be induced to proliferate at high rates d Driven by synergy between DYRK1A inhibitors and TGFb superfamily inhibitors d Reflects activation of cyclins and CDKs accompanied by CDK inhibitor suppression d Proliferation occurs in type 2 diabetic beta cells, with enhanced differentiation SUMMARYSmall-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFbSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax-and SMAD-mediated transactivation of CDKN1C and CDKN1A.Notably, combined DYRK1A and TGFb inhibition allows preservation of beta cell differentiated function. These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.

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Section: Combinations Of Dyrk1a Inhibitors and Tgfbsfmentioning

confidence: 99%

Section: Effects Of R-smads and Trithorax Complex On Cell-cycle Inhibmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

Wang¹,

Karaköse²,

Liu³

et al. 2019

Cell Metabolism

123

209

View full text Add to dashboard Cite

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Pancreatic stellate cell‐potentiated insulin secretion from Min6 cells is independent of interleukin 6‐mediated pathway

Bynigeri

Sasikala

Talukdar

et al. 2019

J of Cellular Biochemistry

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Pancreatic stellate cells (PSCs) secrete various factors, which can influence the β‐cell function. The identification of stellate cell infiltration into the islets in pancreatic diseases suggests possible existence of cross‐talk between these cells. To elucidate the influence of PSCs on β‐cell function, mouse PSCs were cocultured with Min6 cells using the Transwell inserts. Glucose‐stimulated insulin secretion from Min6 cells in response to PSCs was quantified by enzyme‐linked immunosorbent assay and insulin gene expression was measured by quantitative polymerase chain reaction. Upon cytometric identification of IL6 in PSC culture supernatants, Min6 cells were cultured with IL6 to assess its influence on the insulin secretion and gene expression. PLC‐IP3 pathway inhibitors were added in the cocultures, to determine the influence of PSC‐secreted IL6 on Glucose‐stimulated insulin secretion from Min6 cells. Increased insulin secretion with a concomitant decrease in total insulin content was noticed in PSC‐cocultured Min6 cells. Although increased GSIS was noted from IL6‐treated Min6 cells, no change in the total insulin content was noted. Coculture of Min6 cells with PSCs or their exposure to IL6 did not alter either the expression of β‐cell‐specific genes or that of miRNA‐375. PSC‐cocultured Min6 cells, in the presence of PLC‐IP3 pathway inhibitors (U73122, Neomycin, and Xestospongin C), did not revoke the observed increase in GSIS. In conclusion, the obtained results indicate that augmented insulin secretion from Min6 cells in response to PSC secretions is independent of IL6‐mediated PLC‐IP3 pathway.

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Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

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Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID‐19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

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Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors

Cited by 13 publications

References 39 publications

Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells

Pancreatic stellate cell‐potentiated insulin secretion from Min6 cells is independent of interleukin 6‐mediated pathway

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

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