Interspecies comparison reveals Hmga1 as driver of cardiac regeneration [TOMOseq mouse and zebrafish]

The prospect of repairing the heart after a myocardial infarction by promoting cardiomyocyte proliferation has gained momentum from studies showing the heart's regenerative ability in fish, amphibians and neonatal mammals. Despite evidence of varying cardiomyocyte proliferation rates among species, the molecular mechanisms driving cardiomyocyte cell cycle re-entry remain insufficiently understood. In this study, we employed spatial transcriptomics and identified high-mobility group AT-hook 1a (Hmga1a) as being upregulated in cardiomyocytes of the injury border zone in zebrafish, but not in mice. Through knock-out and cardiomyocyte-specific overexpression of hmga1a, we found that Hmga1a was required for zebrafish heart regeneration and sufficient to drive cardiomyocyte proliferation. In addition, a single injection of Hmga1 virus in injured mouse hearts resulted in increased border zone cardiomyocyte proliferation and improved heart function. Mechanistically, Hmga1 expression reduced repressive H3K27me3 histone modifications from developmentally-regulated genes and induced a border zone-like transcriptional program in adult cardiomyocytes. Our study demonstrates the value of interspecies comparisons by identifying Hmga1 as a critical driver of heart regeneration and highlights Hmga1 as a promising therapeutic candidate to improve cardiac repair after injury.