Vasculopathy is a major complication of diabetes. Impaired mitochondrial bioenergetics and biogenesis due to oxidative stress are a critical causal factor for diabetic endothelial dysfunction. Sirt1, an NAD+-dependent enzyme, is known to play an important protective role through deacetylation of many substrates involved in oxidative phosphorylation and reactive oxygen species generation. Mesenchymal stem cell-conditioned medium (MSC-CM) has emerged as a promising cell-free therapy due to the trophic actions of mesenchymal stem cell (MSC)-secreted molecules. In the present study, we investigated the therapeutic potential of MSC-CMs in diabetic endothelial dysfunction, focusing on the Sirt1 signalling pathway and the relevance to mitochondrial function. We found that high glucose-stimulated MSC-CM attenuated several glucotoxicity-induced processes, oxidative stress and apoptosis of endothelial cells of the human umbilical vein. MSC-CM perfusion in diabetic rats ameliorated compromised aortic vasodilatation and alleviated oxidative stress in aortas. We further demonstrated that these effects were dependent on improved mitochondrial function and up-regulation of Sirt1 expression. MSC-CMs activated the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), leading to direct interaction between Akt and Sirt1, and subsequently enhanced Sirt1 expression. In addition, both MSC-CM and Sirt1 activation could increase the expression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α), as well as increase the mRNA expression of its downstream, mitochondrial, biogenesis-related genes. This indirect regulation was mediated by activation of AMP-activated protein kinase (AMPK). Overall our findings indicated that MSC-CM had protective effects on endothelial cells, with respect to glucotoxicity, by ameliorating mitochondrial dysfunction via the PI3K/Akt/Sirt1 pathway, and Sirt1 potentiated mitochondrial biogenesis, through the Sirt1/AMPK/PGC-1α pathway.
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IL-13 induced actin cytoskeleton rearrangement in human podocytes. Magnification, x60, scale bar, 20μm. For more information please see pp. 2317-2327. Image provided by Chan Chang Yien.
Research Article|
October 26 2016
Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway
Yujia Yuan;
Yujia Yuan
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Meimei Shi;
Meimei Shi
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Lan Li;
Lan Li
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Jingping Liu;
Jingping Liu
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Bo Chen;
Bo Chen
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Younan Chen;
Younan Chen
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
†School of Biomedical Sciences, CHIRI Biosciences, Curtin University, GPO Box U1987, Perth, Western Australia, Australia
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Xingxing An;
Xingxing An
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Shuyun Liu;
Shuyun Liu
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Ruixi Luo;
Ruixi Luo
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Dan Long;
Dan Long
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Wengeng Zhang;
Wengeng Zhang
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Philip Newsholme;
Philip Newsholme
†School of Biomedical Sciences, CHIRI Biosciences, Curtin University, GPO Box U1987, Perth, Western Australia, Australia
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Jingqiu Cheng;
Jingqiu Cheng
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Yanrong Lu
*Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
Correspondence: Yanrong Lu (email [email protected]).
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Publisher: Portland Press Ltd
Received:
March 29 2016
Revision Received:
August 15 2016
Accepted:
September 05 2016
Accepted Manuscript online:
September 05 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (23): 2181–2198.
Article history
Received:
March 29 2016
Revision Received:
August 15 2016
Accepted:
September 05 2016
Accepted Manuscript online:
September 05 2016
Citation
Yujia Yuan, Meimei Shi, Lan Li, Jingping Liu, Bo Chen, Younan Chen, Xingxing An, Shuyun Liu, Ruixi Luo, Dan Long, Wengeng Zhang, Philip Newsholme, Jingqiu Cheng, Yanrong Lu; Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway. Clin Sci (Lond) 1 December 2016; 130 (23): 2181–2198. doi: https://doi.org/10.1042/CS20160235
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