Transient overexpression of hPKM2 in porcine cardiomyocytes prevents heart failure after myocardial infarction

作者：Jiacheng Sun, Yalin Wu, Matthew Adjmi, Rachel C. Matthews, Ann Kurian, Magdalena M. Żak, Jimeen Yoo, Gayatri Mainkar, Hannah Lawless, Yu Lu, Patrick Soon‐Shiong, Gregory P. Walcott, Hesham A. Sadek, Jianyi Zhang, Lior Zangi · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65344-4 · 被引用次数：6 · 研究领域：Congenital heart defects research、Cardiac Fibrosis and Remodeling、Pluripotent Stem Cells Research

The adult mammalian heart lacks the ability to regenerate after injury, contributing to heart failure. No current treatment reactivates heart muscle cell division to prevent this decline. We used a targeted, non-viral modified mRNA system to transiently boost expression of a regenerative enzyme, pyruvate kinase muscle isozyme M2, in heart muscle cells of juvenile and adult pig models after ischemic injury. In juvenile pigs treated one-week post-injury, we observed increased markers of cell division, secretion of protective factors, improved heart function, and reduced scarring two months later. In adult pigs treated immediately after injury, we saw improved heart contractility and less fibrosis one month later. These results show that targeted pyruvate kinase muscle isozyme M2 modified mRNA delivery can stimulate muscle regeneration and functional recovery in both young and adult pig hearts. This approach offers a promising strategy for repairing ischemic injury and preventing heart failure in humans. Ischemic heart disease causes irreversible damage due to poor cardiomyocyte renewal. Here, the authors show that PKM2 modRNA therapy in pigs drives cardiomyocyte proliferation, minimizes fibrosis, restores cardiac function and prevents heart failure after injury.