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

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-06-05 DOI:10.1016/j.stem.2024.05.005

Yongshun Lin, Noriko Sato, Sogun Hong, Kenta Nakamura, Elisa A. Ferrante, Zu Xi Yu, Marcus Y. Chen, Daisy S. Nakamura, Xiulan Yang, Randall R. Clevenger, Timothy J. Hunt, Joni L. Taylor, Kenneth R. Jeffries, Karen J. Keeran, Lauren E. Neidig, Atul Mehta, Robin Schwartzbeck, Shiqin Judy Yu, Conor Kelly, Keron Navarengom, Cynthia E. Dunbar

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Abstract

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 in vivo 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.

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自体 iPSC 衍生心肌细胞在两只猕猴体内的长期移植和成熟

用诱导多能干细胞（iPSC-CMs）产生的心肌细胞进行细胞疗法，为治疗慢性缺血性心脏病提供了一条潜在的心脏再生途径。在此，我们报告了自体iPSC-CMs在两只患有小型亚临床慢性心肌梗死的猕猴体内成功实现长期移植和体内成熟的情况，所有这些过程都不需要免疫抑制。使用钠/碘交感器（NIS）报告基因进行的纵向正电子发射断层扫描成像显示，移植物在超过6个月和12个月后保持稳定，没有畸胎瘤形成。组织学分析表明，移植的 iPSC-CMs 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，异体iPSC-CMs在移植后8周内就出现了排斥反应。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，解决了人们对自体 iPSC 疗法新抗原免疫反应性的担忧，并表明自体 iPSC-CMs 同样会在人类心脏中移植和成熟。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.