Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium

Abstract

BackgroundCardiovascular 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 (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts.MethodsA 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.ResultsMetformin 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1057-0) contains supplementary material, which is available to authorized users.

Metformin Increases Proliferative Activity and Viability of Multipotent Stromal Stem Cells Isolated from Adipose Tissue Derived from Horses with Equine Metabolic Syndrome

“…However, the results are in contradiction to data presented by He et al [65], who showed that metformin significantly induces apoptosis of MSCs isolated from human umbilical cord, even at 0.1 mM concentration. He et al showed that metformin induces apoptosis in cells in dose- and time-dependent manner, and indicated that metformin at 2 mM concentration induced a sub-G1 peak, which is a suggestive marker of apoptosis [65]. We confirmed the anti-apoptotic activity of metformin in EqASC cultures at different levels.…”

“…Our results clearly indicate that metformin improves EqASC viability. Additionally, we noted increased transcript levels of the anti-apoptotic BCL-2 gene, in contrast to the findings of He et al [65]. The discrepancy between our findings and those of He et al may be due to the model used, as well as different metformin concentrations.…”

“…The results correlate with our previous findings, showing increased viability of mouse progenitor cells derived from animals treated with metformin [21,22]. However, the results are in contradiction to data presented by He et al [65], who showed that metformin significantly induces apoptosis of MSCs isolated from human umbilical cord, even at 0.1 mM concentration. He et al showed that metformin induces apoptosis in cells in dose- and time-dependent manner, and indicated that metformin at 2 mM concentration induced a sub-G1 peak, which is a suggestive marker of apoptosis [65].…”

Impact of Diabetes Mellitus on Bone Health

“…Studies show decreased osteoclastogenesis in murine-derived preosteoclasts using supra-pharmacological concentrations of metformin [196,197,198]. However, some in vitro studies have shown MSC apoptosis following transplantation and decreased angiogenic potential of human MSCs treated with metformin [199,200]. In human-induced pluripotent MSCs, metformin enhanced osteoblastic activity by increasing ALP activity and mineralized nodule formation, which was partly mediated by the LKB1/AMPK pathway [201].…”

Full title: High glucose protects mesenchymal stem cells from metformin-induced apoptosis through the AMPK-mediated mTOR pathway

“…Recently, our group found a significant decrease in the abundance of circulating MSCs, which was correlated with complications in patients with T 2 DM 19 . In addition, we found the unexpected adverse effect that metformin, as a first-line agent used to treat T 2 DM and a basic glucose-lowering drug used during intensive glucose control, significantly induced MSC apoptosis and damped their therapeutic efficacy in infarcted myocardium 20 . However, the role of glucose during metformin-induced MSC apoptosis in diabetes remains unknown.…”