Abstract | BACKGROUND: METHODS: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. RESULTS:
Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis-associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. CONCLUSIONS: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes.
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Authors | Xiao He, Meng-Wei Yao, Ming Zhu, Dong-Lan Liang, Wei Guo, Yi Yang, Rong-Seng Zhao, Ting-Ting Ren, Xiang Ao, Wei Wang, Chun-Yu Zeng, Hua-Ping Liang, Dong-Po Jiang, Jian Yu, Xiang Xu |
Journal | Stem cell research & therapy
(Stem Cell Res Ther)
Vol. 9
Issue 1
Pg. 306
(11 08 2018)
ISSN: 1757-6512 [Electronic] England |
PMID | 30409193
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cardiotonic Agents
- Metformin
- Adenylate Kinase
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Topics |
- Adenylate Kinase
(metabolism)
- Animals
- Apoptosis
(drug effects)
- Cardiotonic Agents
(metabolism)
- Diabetes Mellitus, Experimental
- Female
- Humans
- Male
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells
(cytology)
- Metformin
(pharmacology)
- Mice
- Myocardial Infarction
(pathology, therapy)
- Treatment Outcome
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