Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium
Abstract 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 th...
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| Format: | Article |
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BMC
2018-11-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-018-1057-0 |
| _version_ | 1818067355893235712 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiao He |
| collection | DOAJ |
| description | Abstract 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 (T2DM), 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 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. |
| first_indexed | 2024-12-10T15:22:22Z |
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| id | doaj.art-53a8879af09540879c78c051e668a54b |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-10T15:22:22Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-53a8879af09540879c78c051e668a54b2022-12-22T01:43:38ZengBMCStem Cell Research & Therapy1757-65122018-11-019111210.1186/s13287-018-1057-0Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardiumXiao He0Meng-Wei Yao1Ming Zhu2Dong-Lan Liang3Wei Guo4Yi Yang5Rong-Seng Zhao6Ting-Ting Ren7Xiang Ao8Wei Wang9Chun-Yu Zeng10Hua-Ping Liang11Dong-po Jiang12Jian Yu13Xiang Xu14Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Cardiology, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Cardiology, Daping Hospital and Research Institute of Surgery, Army Medical UniversityFirst Department, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Critical Care Medicine, Daping Hospital and Research Institute of Surgery, Army Medical UniversityDepartment of Pathology of Pittsburgh Cancer InstituteDepartment of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital and Research Institute of Surgery, Army Medical UniversityAbstract 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 (T2DM), 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 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.http://link.springer.com/article/10.1186/s13287-018-1057-0Mesenchymal stromal cellsMetforminMyocardial infarctionApoptosisDiabetes mellitus |
| spellingShingle | 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 Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium Stem Cell Research & Therapy Mesenchymal stromal cells Metformin Myocardial infarction Apoptosis Diabetes mellitus |
| title | Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| title_full | Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| title_fullStr | Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| title_full_unstemmed | Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| title_short | Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| title_sort | metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium |
| topic | Mesenchymal stromal cells Metformin Myocardial infarction Apoptosis Diabetes mellitus |
| url | http://link.springer.com/article/10.1186/s13287-018-1057-0 |
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