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

Elvira Forte, Daniel A. Skelly, Mandy Chen, Sandra Daigle, Kaesi A. Morelli, Olivia Hon, Vivek M. Philip, Mauro W. Costa, Nadia A. Rosenthal, Milena B. Furtado
2019 Social Science Research Network  
Graphical Abstract Highlights d Longitudinal transcriptional profiling of cardiac interstitial cells post-infarct d Identification of epicardial versus endocardial origin of cardiac stromal cells d A distinct early injury-response signature precedes appearance of myofibroblasts d Modulation of early fibrosis predicts cardiac rupture and pathological remodeling SUMMARY Cardiac ischemia leads to the loss of myocardial tissue and the activation of a repair process that culminates in the formation
more » ... s 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.
doi:10.2139/ssrn.3436216 fatcat:hy6slmlbsfeudabypxonh3dgni