Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression

Lin, Jian-Da; Nishi, Hitoo; Poles, Jordan; Niu, Xiang; McCauley, Caroline; Rahman, Karishma; Brown, Emily J.; Yeung, Stephen T.; Vozhilla, Nicollaq; Weinstock, Ada; Ramsey, Stephen A.; Fisher, Edward A.; Loke, P’ng

doi:10.1172/jci.insight.124574

Cited by 269 publications

(265 citation statements)

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“…However, the specific genes that change in expression were largely non-overlapping between plaques and VAT macrophages (TableS4). This is similar to recent single-cell RNA sequencing of macrophages from plaques and adipose tissue in western diet fed mice (8,12).…”

Section: Discussionsupporting

confidence: 86%

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Inhibiting LXRαPhosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Voisin

Shrestha

Rollet

et al. 2020

Preprint

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Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRa, a nuclear receptor, plays a central role in the transcription of inflammatory and lipid metabolic genes. LXRa is modulated by phosphorylation at serine 196 (LXRa pS196), however, the functional consequences of LXRa pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRa phosphorylation, bone marrow from LXRaWT and S196A mice was transplanted into Ldlr -/mice, which were fed a high fat, high cholesterol diet prior to evaluation

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Section: Discussionsupporting

confidence: 86%

“…Activation of LXRa inhibits atherosclerosis progression in mouse models, which depends in part on LXRa activity in macrophages (3,4). During atherogenesis, immune cellsmostly cholesterol-loaded macrophages accumulate in the arterial wall and form plaques (5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting LXRαPhosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Voisin

Shrestha

Rollet

et al. 2020

Preprint

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“…Analyzing the top genes specific in these clusters and doing a literature search of other single cell analysis, we find that populations similar to those seen in our clusters 1 and 3 have been described ( Supplemental Table 1). Gene signature similar to our cluster 1 has been seen in atherosclerosis 20 and acute lung injury 21 while signatures similar to cluster 3 were seen in myocardial infarction 22 and atherosclerosis 20 .…”

Section: Characterization Of the Inflammatory Niche At The Injury Sitesupporting

confidence: 79%

Regulation of heterotopic ossification through local inflammatory monocytes in a mouse model of aberrant wound healing

Sorkin

Huber

Hwang

et al. 2019

Preprint

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Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic TGFβ levels help ameliorate HO. Our data thus implicate CD47 activation as a novel therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.

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“…We examined expression patterns of FCER1G and TYROBP in several publicly available single cell RNASeq datasets (Figure 4): (A) renal resident macrophages across species (GSE128993; human n = 2,868, mouse n = 3,013, rat n = 3,935, pig n = 4,671) 45 , (B) mouse CX3CR1-derived macrophage from atherosclerotic aorta (GSE123587; n = 5,355) 43 , (C) mouse inflammatory airway macrophages (GSE120000; n = 1,142) 42 , and (D) mouse dissociated whole lung tissue (GSE111664; n = 41,898) 44 . We computed the percentage of single cell sample shows high-high expression patterns with respect to both FCER1G and TYROBP.…”

Section: Resultsmentioning

confidence: 99%

“…To validate our results on single cell RNASeq data we use following datasets: mouse inflammatory airway macrophages (GSE120000; n = 1,142) 42 , mouse CX3CR1-derived macrophage from atherosclerotic aorta (GSE123587; n = 5,355) 43 , mouse dissociated whole lung tissue (GSE111664; n = 41,898) 44 , and renal resident macrophages across species (GSE128993; human n = 2,868, mouse n = 3,013, rat n = 3,935, pig n = 4,671) 45 .…”

Section: Methodsmentioning

confidence: 99%

Computational approach to identifying universal macrophage biomarker

Dang

Taheri

Das

et al. 2019

Preprint

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ABSTRACTMacrophages are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface. Understanding gene expression dynamics in macrophages are crucial for studying human diseases. Recent advances in high-throughput technologies have enabled the collection of immense amounts of biological data. A reliable marker of macrophage is essential to study their function. Traditional approaches use a number of markers that may have tissue specific expression patterns. To identify universal biomarker of macrophage, we used a previously published computational approach called BECC (Boolean Equivalent Correlated Clusters) that was originally used to identify universal cell cycle genes. We performed BECC analysis on a seed gene CD14, a known macrophage marker. FCER1G and TYROBP were among the top candidates which were validated as strong candidates for universal biomarkers for macrophages in human and mouse tissues. To our knowledge, such a finding is first of its kind.CONTRIBUTIONS TO THE FIELDWe have developed a computational approach to identify universal biomarkers of different entities in a biological system. We applied this approach to study macrophages and identified universal biomarkers of this particular cell type. FCER1G and TYROBP were among the top candidates which were validated as strong candidates for universal biomarkers for macrophages in human and mouse tissues. The expression patterns of TYROBP and FCER1G are found to be more homogeneous compared to currently used biomarkers such as ITGAM, EMR1 (F4/80), and CD68. Further, we demonstrated that this homogeneity extends to all the tissues currently profiled in the public domain in multiple species including human and mouse. FCER1G and TYROBP expression patterns were also found to be extremely specific to macrophages found in various tissues. They are strongly co-expressed together. We believe that these two genes are the most reliable candidates of universal biomarker for macrophages.

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Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression

Cited by 269 publications

References 50 publications

Inhibiting LXRαPhosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Inhibiting LXRαPhosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Regulation of heterotopic ossification through local inflammatory monocytes in a mouse model of aberrant wound healing

Computational approach to identifying universal macrophage biomarker

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