Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages

Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin + cardiomyocyte ( Clu + CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, Clu + CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through Cpt1a -dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas Clu overexpression or transplantation of engineered CLU + human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Our findings reveal a critical cardio-immune mechanism whereby Clu + CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.