Transcriptional and epigenetic regulation of macrophages in atherosclerosis

Кузнецова, Т. Н.; Prange, K.H.M.; Glass, Christopher K.; Winther, Menno P.J. de

doi:10.1038/s41569-019-0265-3

Cited by 202 publications

(189 citation statements)

References 122 publications

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“… 67 , 68 Finally, My.2 cells were enriched for anti-inflammatory, foam cell–associated TFs in the scATAC-seq data similar as in the scRNA-seq data. We observed increased chromatin accessibility at loci harboring the KLF4 motif, which next to repressing proinflammatory programs was shown to implement an anti-inflammatory macrophage activation state and is also known to be involved in the transformation of vascular SMCs to macrophages 41 , 46 (Figure 6 F). This is in contrast with the scRNA-seq data where KLF4 was expressed at a low level, indicating that while the KLF4 locus is poised, its associated gene program is not necessarily executed in all foamy macrophages.…”

Section: Resultsmentioning

confidence: 87%

“…Interestingly, My.2 cells expressed smooth muscle actin ( ACTA2 ), a hallmark of smooth muscle cells, in combination with macrophage markers such as LGALS3 and CD68 (Figure VIC and VID in the Data Supplement ). Expression of myeloid lineage TFs (transcription factors) PU.1 (SPI1) and C/EBPß (CEBPB [CCAAT enhancer binding protein beta]) 46 and absence of SMC lineage TFs MYOCD (myocardin) and MRTF-A (MRTFA [myocardin related transcription factor A]) 47 in specifically the ACTA2 + cells of My.2 suggests that part of the My.2 myeloid cells gained characteristics of SMCs rather than that it originated from SMCs 17 (Figure VIE in the Data Supplement ).…”

Section: Resultsmentioning

confidence: 99%

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Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Depuydt

Prange

Slenders

et al. 2020

Circulation Research

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312

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Rationale: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques have not been fully assessed. Objective: Using single-cell transcriptomics and chromatin accessibility we gained a better understanding of the pathophysiology underlying human atherosclerosis. Methods and Results: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4 + and CD8 + T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included two populations of pro-inflammatory macrophages showing IL1B or TNF expression as well as a foam cell-like population expressing TREM2 and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public GWAS data were particularly enriched in lesional macrophages, endothelial and smooth muscle cells. Conclusions: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Depuydt

Prange

Slenders

et al. 2020

Circulation Research

Self Cite

312

386

View full text Add to dashboard Cite

show abstract

“…Innate cells also participate in the development of atherosclerosis. Dysregulation of macrophage and monocyte phenotypes is a major driver of atherosclerosis, in which macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, and cholesterol crystals (55). We observed increased frequency and number of splenic macrophages in the Pbx1d chimeric mice fed with a high-fat diet.…”

Section: Discussionmentioning

confidence: 64%

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

Li¹,

Elshikha²,

Cornaby³

et al. 2020

JCI Insight

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“…Notably, tumor macrophages were enriched for PPARG and MITF activity providing a molecular link to the metabolic phenotype that we noted previously using differential gene expression and pathway analysis. PPARG encodes a member of the peroxisome proliferator-activated receptor family and regulates lipid pathway signaling and the formation of foam cells in atherosclerosis (Kuznetsova et al 2020). The MITF gene is a transcriptional factor that is known to regulate lipid accumulation in adipose tissue macrophages as well as their inflammatory phenotype (Gabriel et al 2014).…”

Section: Metabolically Reprogrammed Mcrc Macrophages Influence Ecm Rementioning

confidence: 99%

Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1⁺ macrophages and fibroblasts

Sathe

Grimes

Lau

et al. 2020

Preprint

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Metastatic colorectal cancer (mCRC) involves tumor cells seeding distant organs. Metastatic CRC genome biology has intrinsic properties related to heterogeneous clonal tumor cells and extrinsic properties of the cellular niche of the tumor microenvironment (TME). To characterize mCRC’s cell types and states, we used single-cell RNA sequencing (scRNA-seq) and DNA sequencing (scDNA-seq) on metastases in the liver and omentum, a tissue lining the abdomen. We performed scRNA-seq on 49,637 cells derived from mCRC, paired normal tissue and peripheral blood. We performed whole genome scDNA-seq on 3,683 mCRC cells from the same samples. These metastases had intrinsic heterogeneity, with clone-specific copy number variation and lineage differentiation. For the extrinsic niche, TME macrophages had a cellular state resembling cirrhotic macrophages and foam cells with indicators of increased activity for extracellular matrix (ECM) organization. TME fibroblasts had an expression program influencing ECM composition that was not observed in matched normal tissue. Only a few CD8 T cells were present among the liver mCRCs, indicating immune exclusion. Receptor-ligand analysis revealed that TME macrophages and fibroblasts formed an interactome, thus providing intercellular coordination which increased T cell exhaustion and exclusion. For one mCRC, we used in a patient-derived ex vivo tissue model that captures the TME components of the original metastatic tumor, applied specific perturbations to the TME immune cells and evaluated cellular state changes with scRNA-seq. Overall, our study identified tumor cell clonal variation, characterized specific TME properties of the CRC metastatic niche and demonstrated an experimental model of perturbing the cellular TME milieu.

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Transcriptional and epigenetic regulation of macrophages in atherosclerosis

Cited by 202 publications

References 122 publications

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1⁺ macrophages and fibroblasts

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Transcriptional and epigenetic regulation of macrophages in atherosclerosis

Cited by 202 publications

References 122 publications

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1+ macrophages and fibroblasts

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Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1⁺ macrophages and fibroblasts