A growing body of evidence indicates that cardiac regeneration after myocardial infarction can be achieved by stimulating the endogenous capacity of cardiomyocytes (CMs) to replicate. This process is controlled, both positively and negatively, by a large set of non-coding RNAs (ncRNAs). Some of the microRNAs (miRNAs) that can stimulate CM proliferation is expressed in embryonic stem cells and is required to maintain pluripotency (e.g. the miR-302∼367 cluster). Others also govern the proliferation of different cell types, including cancer cells (e.g. the miR-17∼92 cluster). Additional miRNAs were discovered through systematic screenings (e.g. miR-199a-3p and miR-590-3p). Several miRNAs instead suppress CM proliferation and are involved in the withdrawal of CMs from the cell cycle after birth (e.g. the let-7 and miR-15 families). Similar regulatory roles on CM proliferation are also exerted by a few long ncRNAs. This body of information has obvious therapeutic implications, as miRNAs with activator function or short antisense oligonucleotides against inhibitory miRNAs or lncRNAs can be administered to stimulate cardiac regeneration. Expression of miRNAs can be achieved by gene therapy using adeno-associated vectors, which transduce CMs with high efficiency. More effective and safer for therapeutic purposes, small nucleic acid therapeutics can be obtained as chemically modified, synthetic molecules, which can be administered through lipofection or inclusion in lipid or polymer nanoparticles for efficient cardiac delivery. The notion that it is possible to reprogramme CMs into a regenerative state and that this property can be enhanced by ncRNA therapeutics remains exciting, however extensive experimentation in large mammals and rigorous assessment of safety are required to advance towards clinical application.

中文翻译：

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用于心脏再生的非编码 RNA 疗法

越来越多的证据表明，心肌梗塞后的心脏再生可以通过刺激心肌细胞 (CM) 的内源性复制能力来实现。这个过程受到大量非编码 RNA (ncRNA) 的正向和负向控制。一些可以刺激CM增殖的微小RNA（miRNA）在胚胎干细胞中表达并且是维持多能性所必需的（例如miR-302∼367簇）。其他也控制不同细胞类型的增殖，包括癌细胞（例如 miR-17∼92 簇）。通过系统筛选发现了其他 miRNA（例如 miR-199a-3p 和 miR-590-3p）。一些 miRNA 反而会抑制 CM 增殖并参与 CM 从出生后的细胞周期中退出（例如 let-7 和 miR-15 家族）。一些长 ncRNA 也对 CM 增殖发挥类似的调节作用。这些信息具有明显的治疗意义，因为可以使用具有激活功能的 miRNA 或针对抑制性 miRNA 或 lncRNA 的短反义寡核苷酸来刺激心脏再生。miRNA 的表达可以通过使用腺相关载体的基因治疗来实现，该载体可以高效地转导 CM。对于治疗目的更有效和更安全，小核酸治疗剂可以作为化学修饰的合成分子获得，这些分子可以通过脂质转染或包含在脂质或聚合物纳米颗粒中进行给药，以实现有效的心脏递送。有可能将 CMs 重新编程为再生状态并且这种特性可以通过 ncRNA 疗法增强的想法仍然令人兴奋，