Angiopoietin-1 enhanced myocyte mitosis, engraftment, and the reparability of hiPSC-CMs for treatment of myocardial infarction
| العنوان: | Angiopoietin-1 enhanced myocyte mitosis, engraftment, and the reparability of hiPSC-CMs for treatment of myocardial infarction |
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| المؤلفون: | Jianyi Zhang, Xin Chen, Shu Uin Gan, Lei Ye, Szejie Loo, Shihua Tan, Zhonghao Tao, Liping Su, Guizhen Tee |
| المصدر: | Cardiovascular Research. 117:1578-1591 |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Time Factors, Physiology, Induced Pluripotent Stem Cells, Myocardial Infarction, Mitosis, Ventricular Function, Left, Fibrin, Andrology, Physiology (medical), Cellular cardiomyoplasty, Angiopoietin-1, Animals, Humans, Regeneration, Medicine, Myocyte, Myocytes, Cardiac, Myocardial infarction, Rats, Wistar, Cells, Cultured, Heart Failure, biology, business.industry, Myocardium, Cell Differentiation, Stroke Volume, Genetic Therapy, Recovery of Function, medicine.disease, Transplantation, Disease Models, Animal, medicine.anatomical_structure, Ventricle, Heart failure, biology.protein, Cardiology and Cardiovascular Medicine, business, Perfusion, Signal Transduction |
| الوصف: | Aims To examine whether transient over-expression of angiopoietin-1 (Ang-1) increases the potency of hiPSC-CMs for treatment of heart failure. Methods and results Atrial hiPSC-CMs (hiPSC-aCMs) were differentiated from hiPSCs and purified by lactic acid and were transfected with Ang-1 (Ang-1-hiPSC-aCMs) plasmid using lipoSTEM. Ang-1 gene transfection efficiency was characterized in vitro. Gene transfected CMs (1x106) were seeded into a fibrin/thrombin patch and implanted on the rat infarcted left ventricular anterior wall after myocardial infarction (MI). Echo function was determined at 1- and 6- weeks post-MI. Immunohistochemistry study was performed at week-6 post-MI. Ang-1 (20 and 40 ng/ml) protected hiPSC-aCMs from hypoxia through up-regulating pERK1/2 and inhibiting Bax protein expressions. Ang-1-hiPSC-aCMs transiently secreted Ang-1 protein up to 14 days, with peak level on day-2 post-transfection (24.39±13.02 ng/ml) in vitro. Animal study showed that transplantation of Ang-1-hiPSC-aCM seeded patch more effectively limited rat heart apoptosis at 1-day post-MI as compared with LipoSTEM-Ang-1 or hiPSC-aCMs transplantation. Ang-1-hiPSC-aCMs transplantation induced host (rat) and donor (human) CM mitosis and arteriole formation, improved cell engraftment rate, more effectively limited left ventricle (LV) dilation (EDV=460.7±96.1 μl and ESV=219.8±72.9 μl) and improved LV global pump function (EF = 53.1±9%) as compared with the MI (EDV=570.9±91.8 μl, p = 0.033; ESV=331.6±71.2 μl, p = 0.011; EF = 42.3±4.1%, p = 0.02) or the LipoSTEM-Ang-1 injected (EDV=491.4±100.4 μl, p = 0.854; ESV=280.9±71.5 μl, p = 0.287; EF = 43.2±4.6, p = 0.039) or hiPSC-CM transplanted (EDV=547.9±55.5 μl, p = 0.095; ESV=300.2±88.4 μl, p = 0.075; EF = 46±10.9%, p = 0.166) animal groups at 6 weeks post-MI and treatment. Conclusions Transient overexpression of Ang-1 enhanced hiPSC-aCM mitosis and engraftment and increased the reparability potency of hiPSC-aCMs for treatment of MI. Translational perspective Cellular cardiomyoplasty using hiPSC-CMs alone may be insufficient to recover the structure and function of infarcted myocardium in which blood vessels and perfusion are damaged. A combinational approach of myogenesis with vasculogenesis to repopulate CMs with functional neovascular network is necessary to recover LV structure and function post-MI. This is the first report showing evidence that transplantation of hiPSC-CM transiently overexpressing Ang-1 had better cell engraftment and improved heart structure and function post-MI. It highlights that transient genetic modification of hiPSC-CMs with Ang-1 using non-viral vectors offers a better CM based angiomyogenesis therapy for treatment of MI. |
| تدمد: | 1755-3245 0008-6363 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e27ddb2fb8d4cc740f38ba6ac88669a3Test https://doi.org/10.1093/cvr/cvaa215Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e27ddb2fb8d4cc740f38ba6ac88669a3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17553245 00086363 |
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