Dynamic Interstitial Cell Response during Myocardial Infarction Predicts Resilience to Rupture in Genetically Diverse Mice

Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation of a scar whose structural characteristics dictate propensity to favorable healing or detrimental cardiac wall rupture. To elucidate the cellular processes underlying scar formation, here we perform unbiased single-cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardial-derived cells. Sixteen interstitial cell clusters are revealed, five of which were of epicardial origin. Focusing on stromal cells, we define 11 sub-clusters, including diverse cell states of epicardial- and endocardial-derived fibroblasts. Comparing transcript profiles from post-infarction hearts in C57BL/6J and 129S1/SvImJ inbred mice, which displays a marked divergence in the frequency of cardiac rupture, uncovers an early increase in activated myofibroblasts, enhanced collagen deposition, and persistent acute phase response in 129S1/SvImJ mouse hearts, defining a crucial time window of pathological remodeling that predicts disease outcome. [Display omitted] •Longitudinal transcriptional profiling of cardiac interstitial cells post-infarct•Identification of epicardial versus endocardial origin of cardiac stromal cells•A distinct early injury-response signature precedes appearance of myofibroblasts•Modulation of early fibrosis predicts cardiac rupture and pathological remodeling Using single-cell transcriptional profiling of mouse hearts carrying a reporter for epicardial-derived cells, Forte et al. provide a dynamic view of cardiac interstitial responses across acute and chronic phases of remodeling post-infarction. Comparing responses on diverse genetic backgrounds reveals novel cellular and transcriptional features of cardiac rupture propensity.