Multi-Omics Integration Reveals Incomplete Reactivation of Developmental Cell-Cycle Programs in Adult Human Infarcted Hearts

Adult human hearts show limited regeneration after acute myocardial infarction (AMI) despite a small subpopulation (~5%) of cardiomyocytes re-entering the cell cycle. We integrated public single-nucleus RNA-seq, spatial transcriptomics, bulk RNA-seq and ATAC-seq datasets from human fetal hearts and adult infarcted hearts to investigate why cell-cycle-active cardiomyocytes fail to complete division. These cells were enriched in the infarct zone (IZ) and activated early cell-cycle programs, but showed insufficient reactivation of late mitotic and cytokinesis execution machinery, particularly ANLN and KIF18A, and instead engaged stress-adaptive programs. Multi-omics filtering across expression, chromatin accessibility, and co-expression/regulatory networks highlighted five developmental cell-cycle-associated genes with insufficient adult reactivation: ANLN, KIF18A, MDK, RTKN2, and SOX11. In human induced pluripotent stem cell-derived cardiomyocytes, hypoxia suppressed most candidates, whereas MDK retained responsiveness to pro-proliferative Wnt stimulation. These findings suggest that incomplete cytokinesis reactivation represents a key bottleneck for adult human cardiac regeneration, and nominate MDK as a tractable candidate for chemical biology and drug-discovery efforts aimed at promoting cardiomyocyte cell-cycle completion.