LARP7 promotes postnatal cardiac regeneration by facilitating G₂/M phase transition

The limited regenerative potential of adult mammalian cardiomyocyte is the biggest hurdle for the heart repair after injury. La Ribonucleoprotein 7 (LARP7), a member of La ribonucleoprotein domain family, is the key regulator of transcription and DNA damage response, but it's role in heart regeneration remains elusive. In this study, the authors discover LARP7 expression level is correlated with myocardial regeneration. Overexpressing LARP7 in the cardiomyocytes moderately promote the cardiomyocyte proliferation and extend the neonatal heart's regenerative window. The mechanism uncovers that LARP7 enhances G₂/M phase transition of cardiomyocyte by suppressing p21 via the SIRT1/p53 pathway and thereby elevating the activity of CDK1/CCNB. To further boost regenerative capacity, The authors co-express CCND1 and CDK4 together with LARP7 using a dual AAV9 system that markedly boosts the cardiac regeneration and facilitates recovery post cardiac damage. In sum, our study unveils LARP7 as a novel molecular switch of cell cycle. LARP7 ectopic expression, especially combining with G₁/S regulators effectively enhances the cardiac regeneration, which underscores LARP7 as a perspective target in cardiac regeneration.