Integrated scRNA-seq analysis identifies conserved transcriptomic features of mononuclear phagocytes in mouse and human atherosclerosis

Abstract

RationaleAccumulation of mononuclear phagocytes (monocytes, macrophages and dendritic cells) in the vessel wall is a hallmark of atherosclerosis. Although single-cell RNA-sequencing (scRNA-seq) has shed new light on immune cell transcriptional diversity in atherosclerosis, it is still unknown whether the transcriptional states of mononuclear phagocytes are conserved between mouse and human atherosclerosis. ObjectiveTo integrate and compare macrophage and dendritic cell transcriptomes in mouse and human atherosclerosis. Methods and resultsWe integrated 12 scRNA-seq datasets of immune cells isolated from healthy or atherosclerotic mouse aortas, and scRNA-seq data from 11 patients (n=4 coronary vessels, n=7 carotid endarterectomy specimens) from two independent studies. Integration of mouse data recovered previously described macrophage populations and identified novel subpopulations with discrete transcriptomic signatures within populations of aortic resident (Lyve1), inflammatory (Il1b), as well as foamy (Trem2hi) macrophages. We identified unique transcriptomic features distinguishing aortic intimal resident macrophages from atherosclerosis-associated Trem2hi macrophages. Also, populations of Xcr1+ type 1 classical dendritic cells (cDC1), Cd209a+ cDC2 and mature DCs (Ccr7, Fscn1) were detected. In humans, we uncovered macrophage and dendritic cell populations with gene expression patterns similar to those observed in mice in both vascular beds. In particular, core transcripts of the foamy/Trem2hi signature (TREM2, SPP1, GPNMB, CD9) mapped to a specific population of macrophages in human lesions. Cross-species data integration demonstrated transcriptionally proximal macrophage and dendritic cell populations in mice and humans. ConclusionsWe demonstrate conserved transcriptomics features of macrophages and dendritic cells in atherosclerosis in mice and humans, emphasizing the relevance of mouse models to study mononuclear phagocytes in atherosclerosis.