Single-Cell Profiling of Dynamic Epicardial Cell States During Myocardial Infarction
Background: The epicardium is reactivated after myocardial infarction (MI); however, the gene expression profiles of post-MI adult epicardial subpopulations remain incompletely defined. Methods: Single-cell RNA sequencing was performed on lineage-traced Wt1+ epicardial cells from Wt1CreERT2/+; R26tdT/+; PdgfranGFP/+ adult mice after sham surgery or at 7 and 14 days after permanent artery ligation…
The epicardium reacts following a myocardial infarction (MI), but the gene expression profiles of post-MI adult epicardial subpopulations are not well understood. To address this knowledge gap, single-cell RNA sequencing was conducted on lineage-traced Wt1+ epicardial cells from adult mice with specific genetic modifications. These mice underwent either sham surgery or permanent artery ligation to induce MI at 7 and 14 days post-surgery.
Immunostaining was also performed on Wt1-lineage-traced cardiac tissue to confirm spatial expression changes after ischemic injury.
The analysis revealed nine transcriptionally distinct epicardial populations. Among these, fibroblast-like epicardial cells (Wt1+/Pdgfra+) exhibited time-dependent expression profiles. At 7 days post-MI, these cells showed upregulation of genes associated with epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) programs. By 14 days post-MI, their expression shifted towards immune regulation, characterized by enrichment of genes related to chemokines and Wnt components.
In contrast, a Wt1high/Msln+ population showed minimal upregulation of EMT gene programs but displayed enhanced paracrine signaling related to wound healing and semaphorins. This suggests a reactivation of reparative and angiogenic functions in the epicardium, similar to what occurs during embryonic development. Immunostaining and in situ hybridization fluorescence analyses confirmed the spatial placement of these epicardial cells after MI, which included a surface Msln+ sheet, an overlapping Wt1-lineage band, and a subadjacent PDGFR+ and Periostin+ compartment that expanded between 7-14 days post-ischemia before regressing by day 28 post-injury.
The findings of this study provide a comprehensive single-cell atlas of epicardial-derived cells at various post-ischemic timepoints. This integrated atlas sheds new light on the reparative potential and dynamic signaling diversity of these cells in the injured adult heart.
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