Injury-Induced CLU-Positive Cardiomyocytes Drive Metabolic Reprogramming of Macrophage Function in Heart Regeneration [Spatial Transcriptomics]

The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.