Combined Treatment with Bone Marrow-Derived Mesenchymal Stem Cells and Exendin-4 Promotes Islet Regeneration in Streptozotocin-Induced Diabetic Rats

Mar 8, 2021Stem cells and development

Bone Marrow Stem Cells and Exendin-4 Together Help Regrow Insulin-Producing Cells in Diabetic Rats

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Abstract

Glucose-induced insulin secretion in the MSC+Ex4 group was significantly increased compared to that in the MSC group.

The combination of bone marrow-derived mesenchymal stem cells (BM-MSC) and the GLP-1 analog exendin-4 (Ex4) may enhance the function of newly formed β-cells in diabetic rats.
The number of insulin-producing cells was greater in the MSC and MSC+Ex4 groups compared to other groups.
The MSC+Ex4 group exhibited significantly higher expression levels of key proteins associated with insulin production (PDX-1, MafA, FoxO1, GLP-1 receptor) than the MSC group.
There was no significant difference in β-cell proliferation and apoptosis between the MSC and MSC+Ex4 groups.
The enhanced function of islet β-cells may be linked to the increased expression of insulin transcription factors following MSC and Ex4 treatment.

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This study was designed to assess whether the combination of the glucagon-like peptide-1 (GLP-1) analog exendin-4 (Ex4) and bone marrow-derived mesenchymal stem cell (BM-MSC) could enhance β-cell action in streptozotocin (STZ)-induced diabetic rats. Forty male Sprague-Dawley rats were randomly assigned to five groups: the normal control group (Normal), diabetes mellitus (DM) group, MSC-treated group (MSC), Ex4-treated group (Ex4), and MSC plus Ex4-treated group (MSC+Ex4). Body weight, blood glucose level, intraperitoneal glucose tolerance test, and in vitro glucose-stimulated insulin secretion were used to assess the treatment efficacy. The expression level of insulin, glucagon, pancreatic duodenal homeobox-1 (PDX-1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), glucagon-like peptide-1 receptor (GLP-1R), and forkhead transcription factor 1 (FoxO1) was estimated by immunofluorescence analysis. Proliferation was assessed by Ki67 staining, and apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in β-cells. Glucose-induced insulin secretion in the MSC+Ex4 group was significantly increased compared to that in the MSC group in vitro and in vivo. Compared to that of the other groups, the number of insulin-immunopositive cells was increased in both the MSC and MSC+Ex4 groups. However, β-cell proliferation and apoptosis in the MSC group and MSC+Ex4 group were not significantly different. Importantly, the expression level of PDX-1, MafA, FoxO1, and GLP-1R in β-cells in the MSC+Ex4 group was significantly higher than those in the MSC group. The numbers of insulinglucagondouble positive cells and glucagonGLP-1double positive cells were significantly increased after MSC treatment and MSC+Ex4 combined treatment, suggesting the enhanced function of newly formed islet β-cells. Our findings showed that the combination of MSC and Ex4 enhanced the function of newly formed β-cells in STZ-induced diabetic rats by acting on multiple insulin transcription factors. Thus, combined MSC and Ex4 therapy provides a feasible approach for future diabetes treatments. + + + +

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Combined Treatment with Bone Marrow-Derived Mesenchymal Stem Cells and Exendin-4 Promotes Islet Regeneration in Streptozotocin-Induced Diabetic Rats

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