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Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro.

ABSTRACT: Mesenchymal stem cells (MSC) are regarded as an attractive source of therapeutic stem cells for myocardial infarction. However, their limited self-renewal capacity, low migration capacity and poor viability after transplantation hamper the clinical use of MSC; thus, a strategy to enhance the biological functions of MSC is required. Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, exerts cell-protective effects on many types of cells. However, little information is available regarding the influence of Ex-4 on MSC. In our study, MSC were isolated from bone marrow and cultured in vitro. After treatment with Ex-4, MSC displayed a higher proliferative capacity, increased C-X-C motif receptor 4 (CXCR4) expression and an enhanced migration response. Moreover, in H2O2-induced apoptosis, Ex-4 preserved mitochondrial function through scavenging ROS and balancing the expression of anti- and pro-apoptotic proteins, leading to the inhibition of the mitochondria-dependent cell death pathways and increased cell survival. Moreover, higher phospho-Akt (p-Akt) expression was observed after Ex-4 intervention. However, blockade of the PI3K/Akt pathway with inhibitors suppressed the above cytoprotective effects of Ex-4, suggesting that the PI3K/Akt pathway is partly responsible for Ex-4-mediated MSC growth, mobilization and survival. These findings provide an attractive method of maximizing the effectiveness of MSC-based therapies in clinical applications.

SUBMITTER: Zhou H

PROVIDER: S-EPMC4528192 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Project description:Osteoblasts are the main functional cells in bone formation, which are responsible for the synthesis, secretion and mineralization of bone matrix. The PI3K/AKT signaling pathway is strongly associated with the differentiation and survival of osteoblasts. The 3‑phosphoinositide‑dependent protein kinase‑1 (PDK‑1) protein is considered the master upstream lipid kinase of the PI3K/AKT cascade. The present study aimed to investigate the role of PDK‑1 in the process of mouse osteoblast differentiation in vitro. In the BX‑912 group, BX‑912, a specific inhibitor of PDK‑1, was added to osteoblast induction medium (OBM) to treat bone marrow mesenchymal stem cells (BMSCs), whereas the control group was treated with OBM alone. Homozygote PDK1flox/flox mice were designed and generated, and were used to obtain BMSCsPDK1flox/flox. Subsequently, an adenovirus containing Cre recombinase enzyme (pHBAd‑cre‑EGFP) was used to disrupt the PDK‑1 gene in BMSCsPDK1flox/flox; this served as the pHBAd‑cre‑EGFP group and the efficiency of the disruption was verified. Western blot analysis demonstrated that the protein expression levels of phosphorylated (p)‑PDK1 and p‑AKT were gradually increased during the osteoblast differentiation process. Notably, BX‑912 treatment and disruption of the PDK‑1 gene with pHBAd‑cre‑EGFP effectively reduced the number of alkaline phosphatase (ALP)‑positive cells and the optical density value of ALP activity, as well as the formation of cell mineralization. The mRNA expression levels of PDK‑1 in the pHBAd‑cre‑EGFP group were significantly downregulated compared with those in the empty vector virus group on days 3‑7. The mRNA expression levels of the osteoblast‑related genes RUNX2, osteocalcin and collagen I were significantly decreased in the BX‑912 and pHBAd‑cre‑EGFP groups on days 7 and 21 compared with those in the control and empty vector virus groups. Overall, the results indicated that BX‑912 and disruption of the PDK‑1 gene in vitro significantly inhibited the differentiation and maturation of osteoblasts. These experimental results provided an experimental and theoretical basis for the role of PDK‑1 in osteoblasts.

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Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro.

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