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Background <p>The transplantation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represents a promising next-generation cell therapy for repairing injured myocardium. However, the safety, efficacy, and pharmacokinetics of these cells in non-human primates (NHPs) with myocardial infarction (MI) have not been systematically investigated.</p> Methods <p>Sixteen rhesus monkeys underwent MI surgery, with 10 monkeys receiving 1 × 10<sup>8</sup> hiPSC-CMs through intramyocardial injection and six monkeys receiving vehicle alone. Echocardiography and cardiac MRI were performed to evaluate the cardiac function and infarct size. A wearable electrocardiogram monitoring device was used to detect postoperative arrhythmias. The bio-distribution of grafted cells in a separate cohort of four monkeys was explored via positron emission tomography/computed tomography (PET/CT) tracking using zirconium 89 (<sup>89</sup>Zr)-prelabeled hiPSC-CMs. Quantitative real-time polymerase chain reaction and immunostaining were used to detect the grafted cells in the host.</p> Results <p>hiPSC-CM transplantation significantly improved cardiac performance at 4 and 12&#xa0;weeks after MI, including left ventricular (LV) ejection fraction, fractional shortening, end-systolic volume, and internal dimension at end-systole. Furthermore, cell transplantation reduced myocardial infarct size, reversed cardiac hypertrophy, and increased angiogenesis 12&#xa0;weeks after MI. Although there was a higher incidence of arrhythmias in the cell therapy group compared to the control group, it was resolved 2&#xa0;weeks after cell transplantation. The survival of multiple islands of human myocardial cells in the host hearts was identified 12&#xa0;weeks after cell implantation, indicating the remuscularization potential of hiPSC-CMs. Consistent with this, PET/CT tracking of <sup>89</sup>Zr-prelabeled hiPSC-CMs showed a high retention of the radioactivity in the heart 2&#xa0;weeks after transplantation. Additionally, the human mitochondrial DNA assay revealed that, except for the heart, no evidence of human cells was observed in the other organs after injection.</p> Conclusions <p>The transplantation of hiPSC-CMs can effectively repair injured cardiac tissue in an NHP MI model without any adverse off-target effects. Therefore, the direct intramyocardial injection of hiPSC-CMs is a promising, effective, and safe strategy for treating MI.</p>

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Human induced pluripotent stem cell–derived cardiomyocytes improve recovery from myocardial infarction in non-human primates

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Xumin Guan,
  • Pengfei Zhang,
  • Qian Wang,
  • Yuehui Zhang,
  • Yunfan Zhang,
  • He Zhang,
  • Hang Zhang,
  • Wanxiang Jiang,
  • Yanxia Wu,
  • Xijie Wang,
  • Dongjin Wang,
  • Jiaxian Wang,
  • Ling Gao

摘要

Background

The transplantation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represents a promising next-generation cell therapy for repairing injured myocardium. However, the safety, efficacy, and pharmacokinetics of these cells in non-human primates (NHPs) with myocardial infarction (MI) have not been systematically investigated.

Methods

Sixteen rhesus monkeys underwent MI surgery, with 10 monkeys receiving 1 × 108 hiPSC-CMs through intramyocardial injection and six monkeys receiving vehicle alone. Echocardiography and cardiac MRI were performed to evaluate the cardiac function and infarct size. A wearable electrocardiogram monitoring device was used to detect postoperative arrhythmias. The bio-distribution of grafted cells in a separate cohort of four monkeys was explored via positron emission tomography/computed tomography (PET/CT) tracking using zirconium 89 (89Zr)-prelabeled hiPSC-CMs. Quantitative real-time polymerase chain reaction and immunostaining were used to detect the grafted cells in the host.

Results

hiPSC-CM transplantation significantly improved cardiac performance at 4 and 12 weeks after MI, including left ventricular (LV) ejection fraction, fractional shortening, end-systolic volume, and internal dimension at end-systole. Furthermore, cell transplantation reduced myocardial infarct size, reversed cardiac hypertrophy, and increased angiogenesis 12 weeks after MI. Although there was a higher incidence of arrhythmias in the cell therapy group compared to the control group, it was resolved 2 weeks after cell transplantation. The survival of multiple islands of human myocardial cells in the host hearts was identified 12 weeks after cell implantation, indicating the remuscularization potential of hiPSC-CMs. Consistent with this, PET/CT tracking of 89Zr-prelabeled hiPSC-CMs showed a high retention of the radioactivity in the heart 2 weeks after transplantation. Additionally, the human mitochondrial DNA assay revealed that, except for the heart, no evidence of human cells was observed in the other organs after injection.

Conclusions

The transplantation of hiPSC-CMs can effectively repair injured cardiac tissue in an NHP MI model without any adverse off-target effects. Therefore, the direct intramyocardial injection of hiPSC-CMs is a promising, effective, and safe strategy for treating MI.