Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques,Cell Stem Cell

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Long-term engraftment and maturation of autologous iPSC-derived cardiomyocytes in two rhesus macaques
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-06-05 , DOI: 10.1016/j.stem.2024.05.005
Yongshun Lin ₁ , Noriko Sato ₂ , Sogun Hong ₃ , Kenta Nakamura ₄ , Elisa A Ferrante ₅ , Zu Xi Yu ₆ , Marcus Y Chen ₇ , Daisy S Nakamura ₄ , Xiulan Yang ₈ , Randall R Clevenger ₉ , Timothy J Hunt ₉ , Joni L Taylor ₉ , Kenneth R Jeffries ₉ , Karen J Keeran ₉ , Lauren E Neidig ₁₀ , Atul Mehta ₅ , Robin Schwartzbeck ₅ , Shiqin Judy Yu ₃ , Conor Kelly ₃ , Keron Navarengom ₅ , Kazuyo Takeda ₁₁ , Stephen S Adler ₁₂ , Peter L Choyke ₂ , Jizhong Zou ₁ , Charles E Murry ₁₃ , Manfred Boehm ₅ , Cynthia E Dunbar ₃

Affiliation

iPSC Core, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Laboratory of Cellular Therapeutics, Molecular Imaging Branch, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.
Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA.
Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
Pathology Core, NHLBI, NIH, Bethesda, MD 20892, USA.
Cardiovascular Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Animal Surgery and Resources Core, NHLBI, NIH, Bethesda, MD 20892, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
Microscopy and Imaging Core, CBER, FDA, Silver Spring, MD, USA.
Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98195, USA.

Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.

中文翻译：

自体 iPSC 衍生心肌细胞在两只恒河猴中的长期植入和成熟

利用诱导多能干细胞 (iPSC-CM) 产生的心肌细胞进行细胞疗法，为心脏再生治疗慢性缺血性心脏病提供了一条潜在途径。在这里，我们报告了自体 iPSC-CM 在两只患有小型亚临床慢性心肌梗死的恒河猴中成功的长期植入和成熟，所有这些都没有免疫抑制。使用钠/碘同向转运体 (NIS) 报告基因的纵向正电子发射断层扫描成像显示移植物稳定超过 6 个月和 12 个月，没有畸胎瘤形成。组织学分析表明移植的 iPSC-CM 能够成熟并与内源性心肌整合，没有免疫细胞浸润或排斥的迹象。相比之下，同种异体 iPSC-CM 在移植后 8 周内被排斥。这项研究提供了迄今为止在任何大型动物模型中最长期的安全性和成熟数据，解决了对自体 iPSC 疗法的新抗原免疫反应性的担忧，并表明自体 iPSC-CM 也将在人类心脏中类似地移植和成熟。

更新日期：2024-06-05

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