Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts
Abstract Background Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation ha...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13287-020-01602-0 |
| _version_ | 1819229888179077120 |
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| author | Xumin Guan Wanzi Xu He Zhang Qian Wang Jiuyang Yu Ruyi Zhang Yamin Chen Yunlong Xia Jiaxian Wang Dongjin Wang |
| author_facet | Xumin Guan Wanzi Xu He Zhang Qian Wang Jiuyang Yu Ruyi Zhang Yamin Chen Yunlong Xia Jiaxian Wang Dongjin Wang |
| author_sort | Xumin Guan |
| collection | DOAJ |
| description | Abstract Background Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. Objectives The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model. Methods Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 107 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas. Results Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4 weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group. Conclusions Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4 weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies. |
| first_indexed | 2024-12-23T11:20:19Z |
| format | Article |
| id | doaj.art-2fac439e3dc94ffe8e309d44d17bf1ba |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-23T11:20:19Z |
| publishDate | 2020-02-01 |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-2fac439e3dc94ffe8e309d44d17bf1ba2022-12-21T17:49:06ZengBMCStem Cell Research & Therapy1757-65122020-02-0111111110.1186/s13287-020-01602-0Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat heartsXumin Guan0Wanzi Xu1He Zhang2Qian Wang3Jiuyang Yu4Ruyi Zhang5Yamin Chen6Yunlong Xia7Jiaxian Wang8Dongjin Wang9Department of Cardiology, The First Affiliated Hospital of Dalian Medical UniversityDepartment of Thoracic and Cardiovascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineDepartment of Thoracic and Cardiovascular Surgery, Peking Union Medical College Nanjing Drum Tower HospitalHELP TherapeuticsHELP TherapeuticsThe Laboratory Animal Center, The First Affiliated Hospital of Nanjing Medical UniversityHELP TherapeuticsDepartment of Cardiology, The First Affiliated Hospital of Dalian Medical UniversityHELP TherapeuticsDepartment of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing UniversityAbstract Background Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. Objectives The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model. Methods Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 107 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas. Results Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4 weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group. Conclusions Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4 weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.http://link.springer.com/article/10.1186/s13287-020-01602-0Human induced pluripotent stem cellCardiomyocytesRegenerative medicineRemodelingHeart failure |
| spellingShingle | Xumin Guan Wanzi Xu He Zhang Qian Wang Jiuyang Yu Ruyi Zhang Yamin Chen Yunlong Xia Jiaxian Wang Dongjin Wang Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts Stem Cell Research & Therapy Human induced pluripotent stem cell Cardiomyocytes Regenerative medicine Remodeling Heart failure |
| title | Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| title_full | Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| title_fullStr | Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| title_full_unstemmed | Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| title_short | Transplantation of human induced pluripotent stem cell-derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| title_sort | transplantation of human induced pluripotent stem cell derived cardiomyocytes improves myocardial function and reverses ventricular remodeling in infarcted rat hearts |
| topic | Human induced pluripotent stem cell Cardiomyocytes Regenerative medicine Remodeling Heart failure |
| url | http://link.springer.com/article/10.1186/s13287-020-01602-0 |
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