Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsets

Mould, Kara J.; Jackson, Nathan D.; Henson, Peter M.; Seibold, Max A.; Janssen, William J.

doi:10.1172/jci.insight.126556

Cited by 166 publications

(175 citation statements)

References 67 publications

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“…We identified one normoxia-specific cluster, Mac.5 (Cluster 11), one partially hyperoxia-specific cluster, Mac.2 (Cluster 3), and one completely hyperoxia-specific macrophage cluster, Mac 4 (Cluster 10). This is in agreement with previously published macrophage clusters by Mould et al 45 .…”

Section: Hyperoxia Exposure Alters Myeloid Cell Distribution and Leasupporting

confidence: 94%

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Hurskainen

Mižíková

Cook

et al. 2019

Preprint

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During late lung development alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia. We observed dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, capillary endothelium and macrophage populations. We identified several BPD-associated signatures, including Pdgfra in fibroblasts, Activin A in capillary endothelial cells, and Csf1-Csf1r and Ccl2-Ccr2 signaling in macrophages and neutrophils. Our data provides a novel single-cell view of cellular changes associated with late lung development in health and in disease.

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Section: Hyperoxia Exposure Alters Myeloid Cell Distribution and Leasupporting

confidence: 94%

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Hurskainen

Mižíková

Cook

et al. 2019

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: 78%

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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“…However, now we know that monocytes continuously traffic through non-lymphoid and lymphoid tissue, where they survey the environment, and unless there is a macrophage niche to fill, steady-state monocytes do not differentiate into self-renewing, tissue resident macrophages 18,19 . During inflammation, monocytes can differentiate into inflammatory and resolving macrophages, which display distinct properties from resident macrophages 10,20,21,22 . In lymphoid tissue, even though LN monocytes are highly present, their role in adaptive immunity is less defined than DCs 19,…”

mentioning

confidence: 99%

Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes

Leach

Gibbings

Tewari

et al. 2020

Preprint

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The mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells (DCs). MP subtypes play distinct functional roles in steady-state and inflammatory conditions. Though murine MPs are well-characterized, their human homologs remain poorly understood. To address this gap, we created a gene expression compendium across 15-distinct human and 9-distinct murine MPs from lung, LN, blood, and spleen. This study identified corresponding human-mouse MP subtypes and determined marker genes shared or not between species counterparts. Unexpectedly, at the gene expression level, only 13-23% of the top 1000 marker genes overlapped in corresponding human-mouse MP counterparts, indicating a need for caution when translating mouse studies to human gene targets and functions. Lastly, CD88 was useful in both species to distinguish macrophage/monocytes from DCs. Our cross-species expression compendium serves as a resource for future translational studies to investigate beforehand whether pursuing specific MP subtypes, or gene will prove fruitful. 12 . Murine pulmonary MPs consist of alveolar macrophages (AMs), tissue trafficking monocytes, dendritic cell (DCs) subtypes 12, 13 , and three interstitial macrophages (IMs):two IMs, IM1-(CD206 hi MHCII + ) and IM2-(CD206 hi MHCII lo ), display classical macrophage characteristics, whereas the third IM, IM3-(CD206 lo MHCII + ), although displaying macrophage properties, has a higher rate of turnover and expresses pro-inflammatory, monocytic and DC genes 7 . Very little is known about IMs, in humans how to identify them, and in both species, humans and mice, how they functionally contribute to homeostasis, inflammation, or disease. Most notably, with the exception of AMs, all other MP subtypes described above reside in multiple organs 14,15,16,17 .Functionally, circulating monocytes traditionally have been viewed as precursors to tissue-resident macrophages. However, now we know that monocytes continuously traffic through non-lymphoid and lymphoid tissue, where they survey the environment, and unless there is a macrophage niche to fill, steady-state monocytes do not differentiate into self-renewing, tissue resident macrophages 18,19 . During inflammation, monocytes can differentiate into inflammatory and resolving macrophages, which display distinct properties from resident macrophages 10,20,21,22 . In lymphoid tissue, even though LN monocytes are highly present, their role in adaptive immunity is less defined than DCs 19, .DCs are potent antigen-presenting cells that link innate and adaptive immunity. In the periphery, DCs can acquire pathogens, traffic through lymphatic vessels to draining LNs, and present exogenous antigens to cognate T cells, precipitating adaptive immunity 11,24,25,26,27 . In mice, there are two main DC types referred to as Batf3 + DC1 and Irf4 +

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Single cell RNA sequencing identifies unique inflammatory airspace macrophage subsets

Cited by 166 publications

References 67 publications

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

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

Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes

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