Involvement of RhoA/ROCK in insulin secretion of pancreatic β-cells in 3D culture

Liu, Xiaofang; Yan, Fangfang; Yao, Hailei; Chang, Ming‐Yang; Qin, Jinhua; Li, Yali; Wang, Yunfang; Pei, Xuetao

doi:10.1007/s00441-014-1961-2

Cited by 20 publications

(17 citation statements)

References 37 publications

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“…Indeed, we found that loss of ROCKII, but not ROCKI, is sufficient to induce the generation and maturation of pancreatic beta-like cells. Although not studied in the context of hESC differentiation, previous studies using rat islets and MIN6 cells are consistent with our finding, suggesting that ROCK inhibitors promote glucose-stimulated insulin secretion 26 , 27 . ROCK signalling has been suggested to function downstream of glucagon-like peptide 1 to rescue glucotoxicity-induced stress fibers 28 .…”

Section: Discussionsupporting

confidence: 91%

ROCKII inhibition promotes the maturation of human pancreatic beta-like cells

et al. 2017

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Diabetes is linked to loss of pancreatic beta-cells. Pluripotent stem cells offer a valuable source of human beta-cells for basic studies of their biology and translational applications. However, the signalling pathways that regulate beta-cell development and functional maturation are not fully understood. Here we report a high content chemical screen, revealing that H1152, a ROCK inhibitor, promotes the robust generation of insulin-expressing cells from multiple hPSC lines. The insulin expressing cells obtained after H1152 treatment show increased expression of mature beta cell markers and improved glucose stimulated insulin secretion. Moreover, the H1152-treated beta-like cells show enhanced glucose stimulated insulin secretion and increased capacity to maintain glucose homeostasis after transplantation. Conditional gene knockdown reveals that inhibition of ROCKII promotes the generation and maturation of glucose-responding cells. This study provides a strategy to promote human beta-cell maturation and identifies an unexpected role for the ROCKII pathway in the development and maturation of beta-like cells.

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Section: Discussionsupporting

confidence: 91%

ROCKII inhibition promotes the maturation of human pancreatic beta-like cells

et al. 2017

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“…RhoA is a member of Rho family of GTPases involved in regulating intracellular actin dynamics ( 36 ). It has been demonstrated that RhoA participates in regulating secretion of insulin ( 37 ), and is associated with insulin resistance via phosphorylation of insulin receptor substrate-1 ( 38 ). Moreover, it also mediates adrenocorticotropin-stimulated cortisol biosynthesis in human adrenocortical cells ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome

Shen

Zhou

Zheng

et al. 2017

International Journal of Molecular Medicine

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The purpose of this study was to identify promising candidate genes and pathways in polycystic ovary syndrome (PCOS). Microarray dataset GSE345269 obtained from the Gene Expression Omnibus database includes 7 granulosa cell samples from PCOS patients, and 3 normal granulosa cell samples. Differentially expressed genes (DEGs) were screened between PCOS and normal samples. Pathway enrichment analysis was conducted for DEGs using ClueGO and CluePedia plugin of Cytoscape. A Reactome functional interaction (FI) network of the DEGs was built using ReactomeFIViz, and then network modules were extracted, followed by pathway enrichment analysis for the modules. Expression of DEGs in granulosa cell samples was measured using quantitative RT-PCR. A total of 674 DEGs were retained, which were significantly enriched with inflammation and immune-related pathways. Eight modules were extracted from the Reactome FI network. Pathway enrichment analysis revealed significant pathways of each module: module 0, Regulation of RhoA activity and Signaling by Rho GTPases pathways shared ARHGAP4 and ARHGAP9; module 2, GlycoProtein VI-mediated activation cascade pathway was enriched with RHOG; module 3, Thromboxane A2 receptor signaling, Chemokine signaling pathway, CXCR4-mediated signaling events pathways were enriched with LYN, the hub gene of module 3. Results of RT-PCR confirmed the finding of the bioinformatic analysis that ARHGAP4, ARHGAP9, RHOG and LYN were significantly upregulated in PCOS. RhoA-related pathways, GlycoProtein VI-mediated activation cascade pathway, ARHGAP4, ARHGAP9, RHOG and LYN may be involved in the pathogenesis of PCOS.

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“…Several studies have indicated Cdc42 and Rac1 GTPases as well as their effector protein PAK1, the GEF protein Tiam1, and RhoGDI as particularly important for glucose-stimulated insulin secretion in vivo and in vitro in mouse β-cells [6] , [13] , [16] , [17] , [18] , [19] . The Rho-ROCK pathway has also been implicated in β-cell function and insulin secretion [17] , [20] , [21] . For instance, pharmacological inhibition of Rho and ROCK leads to a significant increase in actin depolymerization and GSIS in rat primary β-cells and mouse insulinoma 6 (MIN6) cells [20] , [21] .…”

Section: Introductionmentioning

confidence: 99%

The RhoGAP Stard13 controls insulin secretion through F-actin remodeling

Naumann

Rathjen

Poy

et al. 2018

Molecular Metabolism

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ObjectiveActin cytoskeleton remodeling is necessary for glucose-stimulated insulin secretion in pancreatic β-cells. A mechanistic understanding of actin dynamics in the islet is paramount to a better comprehension of β-cell dysfunction in diabetes. Here, we investigate the Rho GTPase regulator Stard13 and its role in F-actin cytoskeleton organization and islet function in adult mice.MethodsWe used Lifeact-EGFP transgenic animals to visualize actin cytoskeleton organization and dynamics in vivo in the mouse islets. Furthermore, we applied this model to study actin cytoskeleton and insulin secretion in mutant mice deleted for Stard13 selectively in pancreatic cells. We isolated transgenic islets for 3D-imaging and perifusion studies to measure insulin secretion dynamics. In parallel, we performed histological and morphometric analyses of the pancreas and used in vivo approaches to study glucose metabolism in the mouse.ResultsIn this study, we provide the first genetic evidence that Stard13 regulates insulin secretion in response to glucose. Postnatally, Stard13 expression became restricted to the mouse pancreatic islets. We showed that Stard13 deletion results in a marked increase in actin polymerization in islet cells, which is accompanied by severe reduction of insulin secretion in perifusion experiments. Consistently, Stard13-deleted mice displayed impaired glucose tolerance and reduced glucose-stimulated insulin secretion.ConclusionsTaken together, our results suggest a previously unappreciated role for the RhoGAP protein Stard13 in the interplay between actin cytoskeletal remodeling and insulin secretion.

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Involvement of RhoA/ROCK in insulin secretion of pancreatic β-cells in 3D culture

Cited by 20 publications

References 37 publications

ROCKII inhibition promotes the maturation of human pancreatic beta-like cells

ROCKII inhibition promotes the maturation of human pancreatic beta-like cells

Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome

The RhoGAP Stard13 controls insulin secretion through F-actin remodeling

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