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

Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J, Chen Y - Sci Rep (2015)

Bottom Line: Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, exerts cell-protective effects on many types of cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.

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.

No MeSH data available.


Related in: MedlinePlus

The PI3K/Akt signaling pathway was required for the MSC proliferation induced by Ex-4.(A and B) MSC were treated with Ex-4 (0–20 nM) for 24 h, and the cell cycle was then evaluated using flow cytometry. (C) Growth curve of MSC after Ex-4 (0–20 nM) intervention from days 1 to 7. (D)After treatment with Ex-4 for 24 h, the protein expression levels of Cyclin D1, Cyclin E, and p-Rb were increased; however, they were decreased by the pre-inhibition of the PI3K/Akt pathway. (E) The EdU assay showed that a blockade of PI3K/Akt could reduce Ex-4-mediated MSC proliferation. *P < 0.05 vs. control group; #P < 0.05 vs. Ex-4 group; LY, LY294002.
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f3: The PI3K/Akt signaling pathway was required for the MSC proliferation induced by Ex-4.(A and B) MSC were treated with Ex-4 (0–20 nM) for 24 h, and the cell cycle was then evaluated using flow cytometry. (C) Growth curve of MSC after Ex-4 (0–20 nM) intervention from days 1 to 7. (D)After treatment with Ex-4 for 24 h, the protein expression levels of Cyclin D1, Cyclin E, and p-Rb were increased; however, they were decreased by the pre-inhibition of the PI3K/Akt pathway. (E) The EdU assay showed that a blockade of PI3K/Akt could reduce Ex-4-mediated MSC proliferation. *P < 0.05 vs. control group; #P < 0.05 vs. Ex-4 group; LY, LY294002.

Mentions: To establish the role of Ex-4 in MSC growth, varying doses of Ex-4 were added to the culture medium for 24 h, and then, the cell cycle distribution was analyzed by flow cytometry. As shown in Fig. 3A,B, an increased fraction of cells of the Ex-4 group were in the S and G2/M phases, and fewer cells were in the G1 phase of the cycle, suggesting that Ex-4 caused a dose-dependent increase in the number of cells undergoing division. To further confirm whether the promotion of the cell cycle by Ex-4 would increase the cellular life span, the effects of Ex-4 on the growth kinetics of MSC at a specified point were assessed using CCK-8. The growth curves shown in Fig. 3C revealed that the growth ability of the MSC improved gradually with increases in the Ex-4 concentration. However, PI3K/Akt inhibition suppressed these effects of Ex-4 on MSC proliferation. Moreover, there were no substantial differences between the control group and the 1-nM group, and, during the first 24 h, no significant differences were found between the groups.


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

Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J, Chen Y - Sci Rep (2015)

The PI3K/Akt signaling pathway was required for the MSC proliferation induced by Ex-4.(A and B) MSC were treated with Ex-4 (0–20 nM) for 24 h, and the cell cycle was then evaluated using flow cytometry. (C) Growth curve of MSC after Ex-4 (0–20 nM) intervention from days 1 to 7. (D)After treatment with Ex-4 for 24 h, the protein expression levels of Cyclin D1, Cyclin E, and p-Rb were increased; however, they were decreased by the pre-inhibition of the PI3K/Akt pathway. (E) The EdU assay showed that a blockade of PI3K/Akt could reduce Ex-4-mediated MSC proliferation. *P < 0.05 vs. control group; #P < 0.05 vs. Ex-4 group; LY, LY294002.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528192&req=5

f3: The PI3K/Akt signaling pathway was required for the MSC proliferation induced by Ex-4.(A and B) MSC were treated with Ex-4 (0–20 nM) for 24 h, and the cell cycle was then evaluated using flow cytometry. (C) Growth curve of MSC after Ex-4 (0–20 nM) intervention from days 1 to 7. (D)After treatment with Ex-4 for 24 h, the protein expression levels of Cyclin D1, Cyclin E, and p-Rb were increased; however, they were decreased by the pre-inhibition of the PI3K/Akt pathway. (E) The EdU assay showed that a blockade of PI3K/Akt could reduce Ex-4-mediated MSC proliferation. *P < 0.05 vs. control group; #P < 0.05 vs. Ex-4 group; LY, LY294002.
Mentions: To establish the role of Ex-4 in MSC growth, varying doses of Ex-4 were added to the culture medium for 24 h, and then, the cell cycle distribution was analyzed by flow cytometry. As shown in Fig. 3A,B, an increased fraction of cells of the Ex-4 group were in the S and G2/M phases, and fewer cells were in the G1 phase of the cycle, suggesting that Ex-4 caused a dose-dependent increase in the number of cells undergoing division. To further confirm whether the promotion of the cell cycle by Ex-4 would increase the cellular life span, the effects of Ex-4 on the growth kinetics of MSC at a specified point were assessed using CCK-8. The growth curves shown in Fig. 3C revealed that the growth ability of the MSC improved gradually with increases in the Ex-4 concentration. However, PI3K/Akt inhibition suppressed these effects of Ex-4 on MSC proliferation. Moreover, there were no substantial differences between the control group and the 1-nM group, and, during the first 24 h, no significant differences were found between the groups.

Bottom Line: Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, exerts cell-protective effects on many types of cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing, China.

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.

No MeSH data available.


Related in: MedlinePlus