Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Health Science Center, Shenzhen University, Shenzhen, China.
Cell Prolif. 2021 Jun;54(6):e13041. doi: 10.1111/cpr.13041. Epub 2021 May 4.
Myocardial infarction (MI) is the most predominant type of cardiovascular diseases with high mortality and morbidity. Stem cell therapy, especially cardiac progenitor cell therapy, has been proposed as a promising approach for cardiac regeneration and MI treatment. Previously, we have successfully generated cardiac progenitor-like cells, induced cardiosphere (iCS), via somatic reprogramming. However, the genome integration characteristic of virus-based reprogramming approach hampered their therapeutic applications due to the risk of tumour formation. In the current study, we aim to establish a safer iCS generation strategy with transgene-free approaches.
Four transgene-free approaches for somatic reprogramming, including episome, minicircle, self-replicative RNA, and sendai virus, were compared, from the perspective of cardiac progenitor marker expression, iCS formation, and cardiac differentiation. The therapeutic effects were assessed in the mouse model of MI, from the perspective of survival rate, cardiac function, and structural alterations.
The self-replicative RNA approach produced more iCS, which had cardiomyocyte differentiation ability and therapeutic effects on the mouse model of MI with comparable levels with endogenous cardiospheres and iCS generated with retrovirus. In addition, the CXCR4 (C-X-C chemokine receptor 4) positive subpopulation of iCS derived cells (iCSDC) delivered by intravenous injection was found to have similar therapeutic effects with intramyocardial injection on the mouse model of MI, representing a safer delivery approach.
Thus, the optimized strategy for iCS generation is safer and has more therapeutic potentials.
心肌梗死（MI）是最主要的心血管疾病类型，具有高死亡率和高发病率。干细胞治疗，特别是心脏祖细胞治疗，已被提出作为心脏再生和 MI 治疗的一种有前途的方法。此前，我们已成功通过体细胞重编程生成了类似于心脏祖细胞的细胞，即诱导心脏球（iCS）。然而，基于病毒的重编程方法的基因组整合特征由于肿瘤形成的风险而阻碍了其治疗应用。在本研究中，我们旨在建立一种更安全的 iCS 生成策略，不使用转基因。
从心脏祖细胞标志物表达、iCS 形成和心脏分化的角度，比较了四种无转基因的体细胞重编程方法，包括附加体、微环、自我复制 RNA 和仙台病毒。从存活率、心功能和结构改变的角度，评估了它们在 MI 小鼠模型中的治疗效果。
自我复制 RNA 方法产生了更多的 iCS，具有心肌细胞分化能力，并对 MI 小鼠模型具有与内源性心脏球和逆转录病毒生成的 iCS 相当的治疗效果。此外，静脉注射的 iCS 衍生细胞（iCSDC）的 CXCR4（C-X-C 趋化因子受体 4）阳性亚群在 MI 小鼠模型中与心肌内注射具有相似的治疗效果，代表了一种更安全的给药方法。
因此，优化的 iCS 生成策略更安全，具有更大的治疗潜力。
