The mammalian heart has a limited regenerative capacity. Previous work suggested the heart can regenerate during development and immediately after birth by inducing cardiomyocyte (CM) proliferation; however, this capacity is lost seven days after birth. modRNA gene delivery, the same technology used successfully in the two mRNA vaccines against SARS-CoV-2, can prompt cardiac regeneration, cardiovascular regeneration and cardiac protection. We recently established a novel CM-specific modRNA translational system (SMRTs) that allows modRNA translation only in CMs. We demonstrated that this system delivers potent intracellular genes (, cell cyclepromoting Pkm2), which are beneficial when expressed in one cell type (, CMs) but not others (non-CMs). Here, we identify Lin28a as an important regulator of the CM cell cycle. We show that Lin28a is expressed in CMs during development and immediately after birth, but not during adulthood. We describe that specific delivery of Lin28a into CM, using CM SMRTs, enables CM cell division and proliferation. Further, we determine that this proliferation leads to cardiac repair and better outcome post MI. Moreover, we identify the molecular pathway of Lin28a in CMs. We also demonstrate that Lin28a suppress Let-7 which is vital for CM proliferation, partially due to its suppressive role on cMYC, HMGA2 and K-RAS.

中文翻译：

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Lin28a心肌细胞特异性修饰的mRNA翻译系统诱导心肌细胞分裂和心脏修复

哺乳动物心脏的再生能力有限。之前的研究表明，心脏可以在发育期间和出生后立即通过诱导心肌细胞（CM）增殖来再生；然而，这种能力在出生后 7 天就会丧失。modRNA基因递送与两种针对SARS-CoV-2的mRNA疫苗中成功使用的技术相同，可以促进心脏再生、心血管再生和心脏保护。我们最近建立了一种新型 CM 特异性 modRNA 翻译系统 (SMRT)，该系统仅允许在 CM 中翻译 modRNA。我们证明，该系统可传递有效的细胞内基因（细胞周期促进 Pkm2），这些基因在一种细胞类型（CM）中表达时是有益的，但在其他细胞类型（非 CM）中表达时则不然。在这里，我们将 Lin28a 确定为 CM 细胞周期的重要调节因子。我们发现 Lin28a 在发育期间和出生后立即在 CM 中表达，但在成年期间不表达。我们描述了使用 CM SMRT 将 Lin28a 特异性递送到 CM 中，使 CM 细胞分裂和增殖。此外，我们确定这种增殖会导致心脏修复和心肌梗死后更好的结果。此外，我们还确定了 Lin28a 在 CM 中的分子途径。我们还证明 Lin28a 抑制对 CM 增殖至关重要的 Let-7，部分原因是其对 cMYC、HMGA2 和 K-RAS 的抑制作用。