Single-Cell Transcriptomics Reveals Dynamic Cellular Interactions and Molecular Mechanisms in Myocardial Infarction Recovery

Abstract

Background

Repair and remodeling following myocardial infarction (MI) are complex processes with a wide array of cellular and molecular mechanisms; however, the cell source mediating repair is still poorly understood in terms of heterogeneity and temporal dynamics.

Methods

We performed a single-cell RNA sequencing (scRNA-seq) analysis of cardiac tissues from different time points post-MI, as well as in gene knockout (ChrisKO) and health control groups. The data were mined by UMAP and t-SNE dimension reduction visualization, pseudotime trajectory analysis, cell communication network analysis, and gene expression pattern cluster.

Results

A collection of cell types contributing to cardiac repair was identified, including fibroblasts, macrophages, endothelial cells, and cardiomyocytes that each expressed gene markers and showed temporal distributions associated with distinct injury phases. Pseudotime trajectory analysis identified a continuous change in cellular state from inflammatory to reparative phase, with immune cells in early stages and tissue repair cells at latter stages. The activation of macrophage migration inhibitory factor (MIF) signaling pathway is highly involved in repair after MI, where chemokine-secreting cells and cardiac fibroblasts act as major MIF signal sources. Network analysis of the intercellular communication revealed that macrophages are key orchestrators of repair. When analyzing branch-specific gene expression, we found that several important regulatory factors including Atpdv1h, Lypla1, Mrpl15, Tcea1, Apoa, Cldn1, Dpep1, and Map had changing trends at different phases during regeneration.

Conclusion

Our study profiled a panoramic landscape of cellular and molecular dynamics after MI at single-cell resolution, demonstrating key cell communication networks and regulatory genes that present novel targets for developing therapeutic strategy toward cardiac repair.