Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2

Liu, Chune; Zhang, Weiwei; Peradze, Natia; Lang, L; Straetener, J; Feilen, Peter J.; Alt, M; Jäger, C; Laubner, Katharina; Perakakis, Nikolaos; Seufert, Jochen; Päth, G

doi:10.1016/j.mce.2018.01.024

Cited by 15 publications

(12 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…34 Similarly, Park et al 35 demonstrated that co-transplantation of human MSC with isolated islets enhanced islet angiogenesis, which could support their survival and proliferation, and this has been linked by others to signaling via the Akt and ERK1/2 pathways in β-cells. 36 It is also possible that MSC induce β-cell neogenesis from the pancreatic ducts following pancreas injury, 37 although this process would be expected to take several weeks before a substantial change in β-cell mass was detected. Additionally, human pancreatic exocrine tissue contains resident MSC that are able to generate endocrine progenitor cell markers following repeated cell passaging in vitro.…”

Section: Discussionmentioning

confidence: 99%

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Arany

Waseem

Strutt

et al. 2018

Islets

View full text Add to dashboard Cite

Both bone marrow-derived hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) improve glycemic control in diabetic mice, but their kinetics and associated changes in pancreatic morphology have not been directly compared. Our goal was to examine the time course of improvements in glucose tolerance and associated changes in β-cell mass and proliferation following transplantation of equivalent numbers of HSC or MSC from the same bone marrow into diabetic non-obese diabetic severe combined immune deficiency (NOD.SCID) mice. We used transgenic mice with a targeted expression of yellow fluorescent protein (YFP) driven by the Vav1 gene promoter to genetically tag HSC and progeny. HSC were separated from bone marrow by fluorescence-activated cell sorting and MSC following cell culture. Equivalent numbers of isolated HSC or MSC were transplanted directly into the pancreas of NOD.SCID mice previously made diabetic with streptozotocin. Glucose tolerance, serum insulin, β-cell mass and β-cell proliferation were examined up to 28 days following transplant. Transplantation with MSC improved glucose tolerance within 7 days and serum insulin levels increased, but with no increase in β-cell mass. Mice transplanted with HSC showed improved glucose tolerance only after 3 weeks associated with increased β-cell proliferation and mass. We conclude that single injections of either MSC or HSC transiently improved glycemic control in diabetic NOD.SCID mice, but with different time courses. However, only HSC infiltrated the islets and were associated with an expanded β-cell mass. This suggests that MSC and HSC have differing mechanisms of action.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Arany

Waseem

Strutt

et al. 2018

Islets

View full text Add to dashboard Cite

show abstract

“…In line with the variety of released growth factors, we and others displayed that MSC-conditioned medium or co-cultured MSC preserve Akt signaling in cultured islets undergoing hypoxic culture stress and additional treatment with alloxan and STZ [135,140]. Akt signaling promotes survival and reduces intrinsic apoptosis by its influence on B-cell lymphoma 2 (Bcl-2) family proteins such as phosphorylation of Bcl-2 antagonist of cell death (BAD) and caspase-9 [141].…”

Section: Humoral Potential Of Mscmentioning

confidence: 94%

“…MSC-released factors also activate mitogenic extracellular signal-regulated kinases (ERK)1/2 signaling which, similar to Akt, promotes survival by inhibition of intrinsic apoptosis [142,143]. Interestingly, MSC induced ERK1/ 2 signaling only in highly proliferative endothelial cells and INS-1E insulinoma cells but not in primary mouse islets with a low proliferation rate [135,140,144]. These observations indicate an important role for the Akt pathway in MSC-mediated survival of pancreatic islets.…”

Section: Humoral Potential Of Mscmentioning

confidence: 99%

Stem cells in the treatment of diabetes mellitus — Focus on mesenchymal stem cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

“…Several recent clinical trials have indicated that mesenchymal stromal cell (MSC)-based therapies are effective in decreasing blood glucose and alleviating some complications such as diabetic foot injuries and diabetic retinopathy [14][15][16][17][18]. MSCs or their conditioned medium not only ameliorate pancreatic β-cell injury [19,20] and islet endothelium apoptosis and functional impairment [21], but also enhance the sensitivity of insulin target tissues [22][23][24]. However, studies showing the direct effect of MSCs on pancreatic α-cell dysfunction are limited.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling

Song

Guo

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Pancreatic α-cells are critical to glucose homeostasis because they release glucagon and stimulate the liver to produce glucose. Dysregulation of α-cells gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin sensitivity in target tissues. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. Methods: In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) involved in glucagon secretion. To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) , AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.Results: In vivo, bmMSC-CM infusion protected against HFD-induced hyperglycemia and hyperglucagonemia. Consistently, bmMSC-CM decreased PA-induced glucagon secretion in α-cells and isolated islets. Additionally, bmMSC-CM reduced intracellular PTEN expression and rescued AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p is highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviates or aggravates glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway. Conclusions: Our observations suggest that MSC-secreted miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling. These findings might provide a novel understanding of MSC-based treatment.

show abstract

Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2

Cited by 15 publications

References 44 publications

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Stem cells in the treatment of diabetes mellitus — Focus on mesenchymal stem cells

Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling

Contact Info

Product

Resources

About

Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2

Cited by 15 publications

References 44 publications

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

Stem cells in the treatment of diabetes mellitus — Focus on mesenchymal stem cells

Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia&nbsp;via miR-181a-5p and its Target PTEN/AKT Signaling

Contact Info

Product

Resources

About

Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling