Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

心脏再生是一项未满足的临床需求，受到成人心肌细胞更新有限和纤维化疤痕的阻碍。基于多能干细胞的策略正在兴起，但揭示宿主-移植物串扰的细胞动力学仍然难以捉摸。在这里，通过在受伤的非人类灵长类动物心脏仿生学中结合谱系追踪和单细胞转录组学，我们揭示了人类祖细胞介导的肌肉修复的协调作用模式。通过 CXCL12/CXCR4 的化学吸引引导细胞迁移到损伤部位。激活的成纤维细胞排斥通过 SLIT2/ROBO1 指导组织细胞骨架动力学来靶向纤维化。最终，分化和机电整合导致受损心肌的功能恢复。体内移植到急性和慢性受伤的猪心脏中，说明了 CXCR4 依赖性归巢、心肌从头形成、疤痕体积减少和预防心力衰竭进展。并发的内皮细胞分化促进了移植物新生血管的形成。我们的研究表明，心脏祖细胞内在的发育程序在疾病中依次被激活，使细胞能够感知和抵消急性和慢性损伤。