Multicellular Communication Networks in Myocardial Ischemia-Reperfusion Injury: Spatial and Temporal Organization of Injury and Repair

Myocardial ischemia–reperfusion injury (MIRI) complicates recovery after acute myocardial infarction despite timely restoration of coronary blood flow. Beyond cardiomyocyte-intrinsic oxidative stress, calcium dysregulation, mitochondrial injury, and regulated cell death, reperfusion simultaneously reorganizes communication among multiple cardiac and extracardiac cell populations. Single-cell and spatial multiomic studies further reveal marked spatial and temporal heterogeneity across the injured heart, although the causal intercellular mechanisms underlying many associations remain incompletely defined. In this Review, we examine MIRI through a multicellular communication framework and discuss interactions among cardiomyocytes, immune cells, endothelial cells, platelets, fibroblasts, vascular mural cells, and extracardiac tissues across the infarct core, border zone, coronary microvascular unit, and remote myocardium. Communication occurs through soluble danger and inflammatory signals, selected metabolites, extracellular vesicles, extracellular matrix and mechanical cues, and direct contact or junctional mechanisms. We distinguish experimentally supported intercellular pathways from spatial associations, parallel responses, and indirect regulatory mechanisms. A spatiotemporally resolved view of these networks may help identify interactions that amplify injury, impair microvascular reperfusion, or participate in resolution and repair, while guiding selective interventions that limit pathological signaling without compromising tissue recovery.