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. 2017 Aug;16(2):1685-1690.
doi: 10.3892/mmr.2017.6832. Epub 2017 Jun 21.

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

Dayong Zhang  1 , Huifei Lu  1 , Zhongxing Chen  1 , Yayan Wang  1 , Jiuzhou Lin  1 , Shan Xu  1 , Chong Zhang  1 , Baoming Wang  1 , Zhanggen Yuan  1 , Xiao Feng  2 , Xuefan Jiang  3 , Jianping Pan  1
Affiliations

High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling

Dayong Zhang et al. Mol Med Rep. 2017 Aug.

Abstract

It has previously been demonstrated that glucose is important in the process of stem cell aging. However, the mechanisms of cell senescence induced by high glucose (HG) remain to be elucidated. The preliminary study indicated that D‑galactose induced mesenchymal stem cell (MSCs) aging. The present study demonstrated, following treatment with 11.0 or 22.0 mM HG for 14 days, that HG significantly promoted MSCs aging and the expression levels of phosphorylated (p-)phosphatidylinositol 3-kinase/protein kinase B (Akt) and p‑mammalian target of rapamycin signaling (mTOR) in the HG groups were increased compared with the control group. However, following Akt inhibition with 1.0 or 10.0 nM MK‑2206, which is an Akt‑specific small molecule inhibitor, the senescence‑cell value in the HG group was significantly decreased compared with the control group. These results indicated that HG induced MSCs senescence and this effect was primarily mediated via the Akt/mTOR signaling pathway.

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Figures

Figure 1.
Figure 1.
Effect of different concentrations of glucose on MSCs senescence. (A) SA-β-gal staining. The number of SA-β-gal-positive cells in the 11.0 mM and 22.0 mM glucose groups increased compared with the control group. SA-β-gal-positive cells exhibit a flat and enlarged cell shape. Scale bar, 25 µm. (B) Quantification of SA-β-gal-positive cells. The total number of SA-β-gal-positive cells of 100 random cells was counted using phase-contrast microscopy. The results demonstrated that the number of SA-β-gal-positive MSCs/100 cells in the 11.0 and 22.0 mM glucose group was significantly increased compared with the control group. *P<0.01 vs. control; n=5. MSCs, mesenchymal stem cells; SA-β-gal, senescence-associated β-galactosidase.
Figure 2.
Figure 2.
Effects of differing concentrations of glucose on the expression of senescence-associated proteins in mesenchymal stem cells. The protein expression levels of p53, p21, p16INK4a were analyzed via western blotting. β-actin served as the internal control. The p53, p21 and p16INK4a expression levels increased in the 11.0 or 22.0 mM glucose groups compared with the control group.
Figure 3.
Figure 3.
Effect of differing concentrations of glucose on MSC proliferation. MSCs were washed and incubated in medium containing various concentrations of glucose for 14 days. Absorbance value was significantly decreased in the 11.0 and the 22.0 mM glucose groups compared with the control group. *P<0.05, #P<0.01. control; n=5. MSCs, mesenchymal stem cells.
Figure 4.
Figure 4.
Effects of high glucose on the Akt/mTOR and Wnt/β-catenin pathway. A total of 14 days following incubation in differing concentrations of glucose, cell lysates were prepared for western blot analysis. The protein expression levels of p-mTOR and p-Akt were increased in the 11.0 and 22.0 mM glucose groups compared with control group, however, the expression levels of p-GSK-3β and β-catenin in the two HG treatment groups appeared to remain unaffected. β-actin served as the internal control. p-, phosphorylated; Akt, protein kinase B; mTOR, mammalian target of rapamycin signaling; GSK, glycogen synthase kinase.
Figure 5.
Figure 5.
Effects of differing concentrations of MK-2206 on HG-induced MSCs senescence. (A) SA-β-gal staining. In the 1.0 and 10.0 nM MK-2206 groups, the number of SA-β-gal-positive cells was decreased compared with that in the HG control group. Scale bar, 25 µm. (B) Quantification of SA-β-gal-positive cells. The total number of SA-β-gal-positive cells among 100 random cells was counted using phase-contrast microscopy. The results demonstrated that the number of SA-β-gal-positive MSCs/100 cells in the 1.0 nM and the 10.0 nM MK-2206 groups was decreased compared with HG control group. (C) Western blot analysis. The p-Akt and p-mTOR expression levels were decreased in the 1.0 and 10.0 nM MK-2206 groups compared with the HG control group. Furthermore, the p53 and p16INK4a expression was decreased in the 1.0 and 10.0 nM MK-2206 groups compared with HG control group. β-actin served as the internal control. *P<0.05, #P<0.01 vs. HG control; n=5. HG, high glucose; SA-β-gal-positive, senescence-associated β-galactosidase-positive; MSCs, mesenchymal stem cells; p-, phosphorylated; Akt, protein kinase B; mTOR, mammalian target of rapamycin signaling.
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References

    1. Schultz MB, Sinclair DA. When stem cells grow old: Phenotypes and mechanisms of stem cell aging. Development. 2016;143:3–14. doi: 10.1242/dev.130633. - DOI - PMC - PubMed
    1. Brunauer R, Kennedy BK. Medicine. Progeria accelerates adult stem cell aging. Science. 2015;348:1093–1094. doi: 10.1126/science.aac4214. - DOI - PubMed
    1. Miura Y. Guest editorial: Human mesenchymal stromal/stem cell (MSC) Int J Hematol. 2016;103:119–121. doi: 10.1007/s12185-015-1931-9. - DOI - PubMed
    1. Asumda FZ. Age-associated changes in the ecological niche: Implications for mesenchymal stem cell aging. Stem Cell Res Ther. 2013;4:47. doi: 10.1186/scrt197. - DOI - PMC - PubMed
    1. de Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F. Immunosuppressive properties of mesenchymal stem cells: Advances and applications. Curr Mol Med. 2012;12:574–591. doi: 10.2174/156652412800619950. - DOI - PubMed

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