二甲双胍可诱导间充质基质细胞凋亡，并减弱其在梗死心肌中的治疗效果。
Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium.
机构信息
Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical University, Chongqing, People's Republic of China.
First Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical University, Chongqing, People's Republic of China.
出版信息
Stem Cell Res Ther. 2018 Nov 8;9(1):306. doi: 10.1186/s13287-018-1057-0.
BACKGROUND
Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (TDM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts.
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 TDM 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.
背景
心血管并发症，尤其是心肌梗死（MI），是糖尿病患者的主要死亡原因。将干细胞移植到受损的心脏已被证明是治疗 MI 的一种有效方法，尽管抗糖尿病药物是否会影响干细胞移植的治疗效果仍不清楚。本研究旨在探讨二甲双胍（一种治疗 2 型糖尿病的一线药物）是否以及如何诱导间充质基质细胞（MSC）凋亡，并减弱其在移植到梗死心脏后的心脏保护作用。
方法
通过永久性结扎左前降支（LAD）冠状动脉建立小鼠 MI 模型。在糖尿病小鼠发生 MI 后，给予或不给予二甲双胍处理的 MSC 移植。通过超声心动图评估心功能并确定心脏重构，通过 TTC 染色评估梗死面积。通过小鼠灌胃模型进行骨髓间充质干细胞的流式细胞术检测。
结果
二甲双胍减弱了 MSC 的治疗效果，增加了梗死面积并限制了功能性心脏恢复。具体来说，二甲双胍通过抑制 S6K1-Bad-Bcl-xL 细胞存活信号通路，激活 AMP 激活的蛋白激酶（AMPK）介导的凋亡，导致凋亡相关蛋白表达上调和 MSC 凋亡增加。因此，拮抗 AMPK 可减弱二甲双胍诱导的 MSC 凋亡，并部分恢复其在糖尿病合并 MI 小鼠中的心脏保护作用。此外，还发现患有 TDM 并接受二甲双胍治疗的患者外周血 MSCs 减少。
结论
我们的研究结果强调了二甲双胍通过 AMPK 介导的 mTOR 抑制诱导 MSC 凋亡的意外不良作用，而 AMPK 抑制剂可减轻这种作用。此外，AMPK 抑制可能是增强糖尿病患者 MI 后干细胞治疗效果的一种新策略。
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