Single-cell and extracellular vesicle profiling reveals fibroblast-macrophage crosstalk in epicardial adipose tissue during acute myocardial infarction
L Zhao, H Sun, Y S Peng, Z S Guo, Y P Zhang, Y L Guo, J Zhang, H S Wang, P X Su, L ZhaoAbstract
Background
Epicardial adipose tissue (EAT) modulates coronary atherosclerosis via paracrine signalling. We aimed to define the cellular heterogeneity and extracellular vesicle (EV)-mediated crosstalk within human EAT during acute myocardial infarction (AMI).
Methods
We integrated single-cell RNA sequencing (scRNA-seq) and EV transcriptomic profiling of EAT from patients with AMI , unstable angina (UA), and non-coronary artery disease (non-CAD). Analyses included clustering, pseudotime trajectory inference, cell-cell communication (CellChat), and computational deconvolution of EV cellular origins.
Results
scRNA-seq revealed a dramatic shift in EAT cellularity during AMI, characterised by a 3.3-fold expansion of fibroblasts (dominated by profibrotic SPSB1+ and IGLC2+ subsets) and significant infiltration of myeloid cells, alongside a marked reduction in endothelial cells. Pseudotime analysis indicated inflammatory reprogramming of these key populations. Cell-cell communication analysis identified significantly reinforced fibroblast-macrophage crosstalk in AMI, primarily mediated by ECM ligand-receptor pairs FN1-CD44 and COL1A2-CD44. EV cargo analysis showed enrichment for TNF, mTOR, and IL-17 signalling pathways in AMI. Bioinformatic deconvolution suggested a shift in the predominant EV source from immune cells in UA to activated fibroblasts (~68% contribution) in AMI, with their cargo enriched for lipid metabolism and oxidative stress genes.
Conclusion
This study unveils an AMI-specific cellular and vesicular axis within EAT, featuring expanded profibrotic fibroblasts engaging reinforced crosstalk with macrophages. The concomitant shift towards a fibroblast-dominated EV profile suggests a novel paracrine mechanism. These findings highlight potential diagnostic and therapeutic targets within the EAT microenvironment for post-infarction remodelling.ScRNA-seq analyses of EATCellular origin analysis of EVs