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.
Highlights
We examined whether the modulatory role of Ex-4 in mesenchymal stem cells (MSC) was due to the activation of the PI3K/Akt signaling pathway
We found that blocking the SDF-1/C-X-C motif receptor 4 (CXCR4) interaction with AMD3100 completely abolished the migration response of MSC, showing that SDF-1/CXCR4 was necessary for MSC migration
It has been reported that 99% of transplanted cells are lost after transplantation[39,40] because of cellular apoptosis, nutrient deprivation and the inflammatory response[41]
Summary
These attempts have obtained exciting and promising results, the high cost and potential side effects of these strategies have limited their applications. Researchers have recently found that Ex-4 promotes the proliferation or survival of many types of cells[17,18] via GLP-1R-dependent and -independent pathways[19,20]. Little information is available regarding the effects of Ex-4 on MSC biological functions. We observed beneficial effects of Ex-4 on MSC proliferation, migration and survival. We examined whether the modulatory role of Ex-4 in MSC was due to the activation of the PI3K/Akt signaling pathway
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