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

• Published in: Cell reports (Cambridge) Vol. 30; no. 9; pp. 3149 - 3163.e6
• Main Authors: Forte, Elvira, Skelly, Daniel A., Chen, Mandy, Daigle, Sandra, Morelli, Kaesi A., Hon, Olivia, Philip, Vivek M., Costa, Mauro W., Rosenthal, Nadia A., Furtado, Milena B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2020; Cell Press; Elsevier
• Subjects: Animals; cardiac rupture; Cicatrix - pathology; epicardial-derived; fibrosis; genetic diversity; heart; Homeostasis; Mice; Mice, Inbred Strains; mouse; myocardial infarction; Myocardial Infarction - genetics; Myocardium - pathology; Myofibroblasts - pathology; Pericardium - pathology; Phenotype; RNA-Seq; Rupture - pathology; scRNAseq; Seurat; Single-Cell Analysis; single-cell biology; Stromal Cells - pathology; cardiac rupture; genetic diversity; mouse; single-cell biology; myocardial infarction; fibrosis; Seurat; scRNAseq; heart; epicardial-derived
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.02.008

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.