Kishino Yoshikazu, Fukuda Keiichi
Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Biomedicines. 2023 Mar 15;11(3):915. doi: 10.3390/biomedicines11030915.
Patients with chronic heart failure (HF) have a poor prognosis due to irreversible impairment of left ventricular function, with 5-year survival rates <60%. Despite advances in conventional medicines for HF, prognosis remains poor, and there is a need to improve treatment further. Cell-based therapies to restore the myocardium offer a pragmatic approach that provides hope for the treatment of HF. Although first-generation cell-based therapies using multipotent cells (bone marrow-derived mononuclear cells, mesenchymal stem cells, adipose-derived regenerative cells, and c-kit-positive cardiac cells) demonstrated safety in preclinical models of HF, poor engraftment rates, and a limited ability to form mature cardiomyocytes (CMs) and to couple electrically with existing CMs, meant that improvements in cardiac function in double-blind clinical trials were limited and largely attributable to paracrine effects. The next generation of stem cell therapies uses CMs derived from human embryonic stem cells or, increasingly, from human-induced pluripotent stem cells (hiPSCs). These cell therapies have shown the ability to engraft more successfully and improve electromechanical function of the heart in preclinical studies, including in non-human primates. Advances in cell culture and delivery techniques promise to further improve the engraftment and integration of hiPSC-derived CMs (hiPSC-CMs), while the use of metabolic selection to eliminate undifferentiated cells will help minimize the risk of teratomas. Clinical trials of allogeneic hiPSC-CMs in HF are now ongoing, providing hope for vast numbers of patients with few other options available.
慢性心力衰竭（HF）患者由于左心室功能的不可逆损害，预后较差，5年生存率<60%。尽管用于HF的传统药物取得了进展，但预后仍然不佳，因此需要进一步改善治疗方法。基于细胞的心肌修复疗法提供了一种切实可行的方法，为HF的治疗带来了希望。虽然第一代基于多能细胞（骨髓来源的单个核细胞、间充质干细胞、脂肪来源的再生细胞和c-kit阳性心脏细胞）的细胞疗法在HF的临床前模型中证明了安全性，但低植入率以及形成成熟心肌细胞（CMs）并与现有CMs电偶联的能力有限，这意味着双盲临床试验中心脏功能的改善有限，且很大程度上归因于旁分泌效应。下一代干细胞疗法使用源自人类胚胎干细胞或越来越多地源自人类诱导多能干细胞（hiPSCs）的CMs。这些细胞疗法在临床前研究中，包括在非人类灵长类动物中，已显示出更成功植入并改善心脏机电功能的能力。细胞培养和递送技术的进步有望进一步提高hiPSC衍生的CMs（hiPSC-CMs）的植入和整合，而使用代谢筛选来消除未分化细胞将有助于将畸胎瘤风险降至最低。目前正在进行异体hiPSC-CMs治疗HF的临床试验，为大量几乎没有其他选择的患者带来了希望。
