Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis

Abstract

These data unprecedentedly uncovered the transcriptional landscape and phenotypic heterogeneity of aortic macrophages and monocyte-derived dendritic cells in atherosclerotic and identified previously unrecognized macrophage populations and their gene expression signature, suggesting specialized functions. Our findings will open up novel opportunities to explore distinct myeloid cell populations and their functions in atherosclerosis.

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

“…To evaluate whether similar neutrophil diversity could be observed in a distinct cardiovascular disease context, we analyzed scRNA-seq data from 2106 CD45 + cells isolated from control (371 cells) and atherosclerotic (1735 cells) aortas of Low densitiy lipoprotein receptor deficient (Ldlr-/-) mice (corresponding to a previously published dataset combined with novel data, see ref (16), and methods) ( Figure S8). Although only 66 cells corresponding to neutrophils were observed (Figure S8A), expression of the characteristic transcripts Siglecf and Icam1 appeared to localize to a subpopulation with segregated tSNE coordinates (Figure S8B-D).…”

“…Diet-induced atherosclerosis was performed in Ldlr -/mice as previously described in ref (16). After 10 weeks of high fat diet feeding, macroscopically visible plaques were mechanically removed from aortas.…”

“…The recent development of single-cell RNA-sequencing (scRNA-seq) in highthroughput allows investigating immune cell transcriptional states in disease models with high resolution, and has recently been employed to uncover novel immune cell transcriptional states in e.g. myocardial infarction (13), (14) or atherosclerosis (15), (16). Furthermore, novel methods of oligonucleotide-barcoded antibody labeling of cells prior to their processing for scRNA-seq allows a multimodal measurement of the expression of cell surface epitopes in addition to transcripts expression (17), (18) and the multiplexing of several biological samples in a single scRNA-seq library (19).…”

GATA2 Expression by Intima-Infiltrating Macrophages Drives Early Atheroma Formation

“…For example, classically polarized M1 and M2 macrophages undergo rapid repolarization via a Nrf2-driven transcriptional program into an atherogenic polarization state upon exposure to moLDL 31 . In this study, we determined that macrophages isolated from early-stage human atheromas lack upregulation of classical M1 (CD80/86, iNOS) or M2 (Arg1, CD206) markers, or markers previously reported in macrophage polarization states present in late-stage plaque (TREM2, Nrf2, Atf1) 27,30,31 . Instead, these cells downregulated many genes involved in the processes of efferocytosis, cholesterol processing, and the degradative pathway required for proper removal of both apoptotic cells and moLDL, while upregulating immunogenic enzymes such as PADI3.…”

“…In mice, resident aortic macrophages are embryonically-derived, self-renewing cells characterized by the expression of scavenger receptors, MHC II and efferocytic receptors 22 . In mouse models two macrophage sub-types emerge within atherosclerotic lesions: haematopoietically-derived inflammatory (M1) macrophages, and a TREM2 + population unique to the atherosclerotic plaque that expresses a mixture of resident-macrophage markers and markers of alternatively activated (M2) cells 27 . While the ontology of human aortic and cardiac macrophages are not well-understood, macrophages with markers of M1-polarization (iNOS, CD86), M2-polarization (MR, dectin-1), and TREM2 + -polarization (TREM2, CD9 hi ) have been identified in established plaques 27,28 .…”