Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function

Xu, Wei; Liang, Jun; Geng, Hao; Lü, Jun; Li, Rui; Wang, X. L.; Lei, Qian; Liu, Ying; Wang, Jie; Liu, X. K.; Jones, Peter M.; Sun, Zilin

doi:10.1155/2019/7870109

Cited by 11 publications

(19 citation statements)

References 33 publications

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“…The present clinical study also identified that Wnt5a was significantly downregulated in newly diagnosed type 2 diabetes mellitus patients. An in vitro study showed that Wnt5a could increase the level of insulin when ISCs are co-cultured with islet b-cells 41 . In the present study, we showed that Wnt5a, Fzd5, bcatenin, Ror2 and P-CamKII were expressed in ISCs, albeit at a relatively high level under normoglycemic conditions.…”

Section: Discussionmentioning

confidence: 99%

Wingless‐type MMTV integration site family member 5a is a key inhibitor of islet stellate cells activation

Geng

Liang

et al. 2019

J of Diabetes Invest

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Aims/Introduction Type 2 diabetes mellitus is a chronic metabolic disorder characterized by islet β‐cell dysfunction, which might result from the activation of islet stellate cells (ISCs). Our recent study showed that a specific population of ISCs is prone to be activated in type 2 diabetes mellitus accompanied by reduced secretion of insulin. The wingless‐type MMTV integration site family member 5a (Wnt5a)/frizzled‐5 signaling pathway might play an important role in this process. The present study aimed to explore the effects of Wnt5a on the activation of ISCs isolated from db/db mice. Materials and Methods ISCs were isolated from db/db mice and matched db/m mice. Immunohistochemistry and western blotting analysis were applied for the determination of Wnt5a expression. Exogenous Wnt5a and lentivirus containing the target gene Wnt5a short hairpin ribonucleic acid were used as a molecular intervention. The experiment of transwell and wound healing was used to evaluate the migration of the isolated ISCs. Results Our data showed that the expression of Wnt5a and frizzled‐5 was decreased in the ISCs isolated from db/db mice compared with db/m mice. Both the exogenous Wnt5a and the overexpression of Wnt5a could inhibit the outgrowth rate of ISCs from islets, and its viability, migration and α smooth muscle actin expression. These changes were associated with the inactivation of the Smad2/3 signaling pathway in a frizzled‐5‐dependent manner. Conclusions Our observations revealed a potential role of Wnt5a in preventing ISC activation. The maintenance of quiescent ISCs might be a desirable outcome of therapeutic strategies for diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Wingless‐type MMTV integration site family member 5a is a key inhibitor of islet stellate cells activation

Geng

Liang

et al. 2019

J of Diabetes Invest

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“…To confirm the Wnt5a protein expression in pancreatic samples (from 8, 20, and 28-weekold mice), immunohistochemistry was performed as described previously [7]. Mouse pancreases were fixed in 4% paraformaldehyde in 0.1M PBS for 24 h at 4°C, embedded in paraffin, and sectioned.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…, Insulin, Glucagon, and Desmin. Immunofluorescence microscopy was performed as described previously [7] to evaluate the expression of Wnt5a and its receptor Frizzled5 (Fzd5) in Min6 cells, and insulin, glucagon, and desmin in islets. Immunostaining was performed with polyclonal antibodies specific for Wnt5a, Fzd5, insulin, glucagon, and desmin (1 : 200, Abcam, Cambridge, UK).…”

Section: Immunofluorescence Microscopy Of Wnt5a Frizzled5mentioning

confidence: 99%

“…A clinical study by our team showed that the serum Wnt5a level was significantly decreased in newly diagnosed T2DM patients compared with normal controls [17]. In addition, exogenous Wnt5a inhibited the activation of ISCs and increased insulin secretion from islets [7,18]. e FoxO1 and Pdx1-Glut2insulin pathway plays an important role in glucosestimulated insulin secretion (GSIS) [19].…”

Section: Introductionmentioning

confidence: 99%

“…Vascular endothelial cells participate in pancreatic development and affect islet morphology and function [6]. Previous studies showed that insulin secretion from islets cocultured in vitro with quiescent ISCs from db/m mice is significantly increased compared to that from islets cultured with activated ISCs from db/db mice and revealed that ISCs regulate β-cell function via Wnt5a [7]. However, the mechanism by which ISCs mediate β-cell insulin secretion homeostasis via Wnt5a has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

Jones

Geng

et al. 2020

International Journal of Endocrinology

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Background. Type 2 diabetes mellitus is a serious public health problem worldwide. Accumulating evidence has shown that β-cell dysfunction is an important mechanism underlying diabetes mellitus. e changes in the physiological state of islet stellate cells (ISCs) and the effects of these cells on β cell function play an important role in the development of diabetes. is study aimed at elucidating the mechanism by which ISCs regulate insulin secretion from Min6 cells via the Wnt5a protein. Methods. Glucosestimulated insulin secretion (GSIS) from Min6 cells was examined by estimating the insulin levels in response to high glucose challenge after culture with ISC supernatant or exogenous Wnt5a. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to observe changes in the β-catenin, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Ca (2+)/calmodulin (CaM)-dependent protein kinase II (CamKII), forkhead box O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX1), glucose transporter 2 (Glut2), insulin, and Cask mRNA and protein levels in the Wnt and insulin secretory pathways. Flow cytometry was used to confirm the intracellular Ca 2+ concentration in Min6 cells. Results. We observed a significant increase in insulin secretion from Min6 cells cocultured in vitro with supernatant from db/m mouse ISCs compared to that from Min6 cells cocultured with supernatant from db/db mouse ISCs; e intracellular Ca 2+ concentration in Min6 cells increased in cultured in vitro with supernatant from db/m mouse ISCs and exogenous Wnt5a compared to that from control Min6 cells. Culture of Min6 cells with exogenous Wnt5a caused a significant increase in pCamKII, pFoxO1, PDX-1, and Glut2 levels compared to those in Min6 cells cultured alone; this treatment further decreased Ror2 and Cask expression but did not affect β-catenin expression. Conclusion. ISCs regulate insulin secretion from Min6 cells through the Wnt5a protein-induced Wntcalcium and FoxO1-PDX1-GLUT2-insulin signalling cascades.

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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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Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function

Cited by 11 publications

References 33 publications

Wingless‐type MMTV integration site family member 5a is a key inhibitor of islet stellate cells activation

Wingless‐type MMTV integration site family member 5a is a key inhibitor of islet stellate cells activation

Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells

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

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