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

Abstract

Cardiac ischemia leads to loss of myocardial tissue and 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 we performed unbiased single cell mRNA sequencing of interstitial cells isolated from infarcted mouse hearts carrying a genetic tracer that labels epicardium, the major source of cardiac fibroblasts. Sixteen interstitial cell clusters were revealed, five of which were of epicardial origin. Focusing on stromal cells, we defined eleven 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 displaying a marked divergence in frequency of cardiac rupture uncovered 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.