Spatial Transcriptomic Profiling Reveals Niche-Governed Efferocytosis-Related Gene Signatures and Degradation-Phase Dysregulation in Myocardial Infarction

Clearing dying cardiomyocytes by efferocytosis is required for inflammation resolution and cardiac repair after myocardial infarction (MI). Whether the three functional stages of efferocytosis (recognition, engulfment and degradation) are coordinated by the local cellular neighborhood in the human infarcted myocardium is unknown. We analyzed 24 human cardiac Visium spatial transcriptomic samples (20 MI, 4 control; 94,029 spots; 19 independent donors) from a published multi-omic map of human MI^[4]. Multiview interaction-based spatial transcriptomics (MISTy) identified 12 gene programs with spot-level neighborhood dependency; donor-level aggregation showed positive neighborhood gains for 22 of 23 programs after Benjamini-Hochberg correction (FDR < 0.05), including all three efferocytosis stages[5]. Efferocytosis module activity tracked macrophage proportions (Spearman rho = 0.41-0.44). Controlling for macrophage abundance removed the engulfment-related association but left a degradation-related association with endothelial and fibroblast proportions, indicating niche-dependent regulation of the degradation stage. Distance-stratified analysis showed neighborhood effects beyond direct cell-cell contact, without simple short-range dominance. Mendelian randomization linked NR1H3, STAU1, CTSS and ITGAV expression to MI risk (FDR < 0.05)[14], and connectivity-map analysis nominated niclosamide as a candidate for reversing the efferocytosis-degradation program[15]. Model-based in silico perturbation attributed the neighborhood dependency to vascular-stromal neighbors; virtual knockout of NR1H3 predicted coordinated downregulation of efferocytosis genes. Efferocytosis subprograms are thus spatially decoupled in the human infarcted myocardium, with degradation as a niche-regulated step, providing spatial and genetic leads for targeting infarct repair.