Integrated analysis of multimodal single-cell data

Cell, Год журнала: 2021, Номер 184(13), С. 3573 - 3587.e29

Опубликована: Май 31, 2021

The simultaneous measurement of multiple modalities represents an exciting frontier for single-cell genomics and necessitates computational methods that can define cellular states based on multimodal data. Here, we introduce "weighted-nearest neighbor" analysis, unsupervised framework to learn the relative utility each data type in cell, enabling integrative analysis modalities. We apply our procedure a CITE-seq dataset 211,000 human peripheral blood mononuclear cells (PBMCs) with panels extending 228 antibodies construct reference atlas circulating immune system. Multimodal substantially improves ability resolve cell states, allowing us identify validate previously unreported lymphoid subpopulations. Moreover, demonstrate how leverage this rapidly map new datasets interpret responses vaccination coronavirus disease 2019 (COVID-19). Our approach broadly applicable strategy analyze look beyond transcriptome toward unified definition identity.

Язык: Английский

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A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Авг. 16, 2022

Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment bone biopsies from two aged human cohorts. We further demonstrate reductions SenMayo following genetic clearance of cells mice adipose tissue humans pharmacological clearance. next use to identify hematopoietic or mesenchymal at single level murine marrow/bone scRNA-seq data. Thus, identifies across tissues species with high fidelity. Using this panel, are able characterize key intercellular signaling pathways. also represents potentially clinically applicable panel for monitoring burden aging other conditions as well studies senolytic drugs.

Язык: Английский

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Spatial multi-omic map of human myocardial infarction

Nature, Год журнала: 2022, Номер 608(7924), С. 766 - 777

Опубликована: Авг. 10, 2022

Язык: Английский

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Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

Nature Medicine, Год журнала: 2021, Номер 28(1), С. 201 - 211

Опубликована: Ноя. 15, 2021

Abstract Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects dexamethasone severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, bacterial was associated with expansion distinct neutrophil states characterized by interferon (IFN) prostaglandin signaling. Dexamethasone affected circulating neutrophils, altered IFN active downregulated interferon-stimulated genes activated IL-1R2 + neutrophils. expanded immunosuppressive immature neutrophils remodeled cellular interactions changing information receivers into providers. Male patients had higher proportions preferential steroid-induced expansion, potentially affecting outcomes. Our atlas (see ‘Data availability’ section) defines COVID-19-enriched molecular action develop targeted immunotherapies COVID-19.

Язык: Английский

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Single-cell meta-analyses reveal responses of tumor-reactive CXCL13+ T cells to immune-checkpoint blockade

Nature Cancer, Год журнала: 2022, Номер 3(9), С. 1123 - 1136

Опубликована: Сен. 22, 2022

Язык: Английский

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Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation

Science Immunology, Год журнала: 2023, Номер 8(82)

Опубликована: Апрель 7, 2023

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying populations found human fibrotic tissues could lead new treatments for fibrosis. Here, we used liver lung single-cell RNA sequencing datasets identify a subset CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, CD63. In both murine hepatic pulmonary fibrosis, these were enriched at outside edges scarring adjacent activated mesenchymal cells. Neutrophils expressing MMP9, which participates TGF-β1, type 3 cytokines GM-CSF IL-17A coclustered macrophages. vitro, GM-CSF, IL-17A, TGF-β1 drive differentiation monocytes into scar-associated markers. Such differentiated cells degrade collagen IV but not I promote TGF-β1-induced deposition by models blocking or reduced expansion Our work identifies highly specific population assign profibrotic role across species tissues. It further provides strategy unbiased discovery, triage, preclinical validation therapeutic targets based on this fibrogenic population.

Язык: Английский

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Epigenetic memory of coronavirus infection in innate immune cells and their progenitors

Cell, Год журнала: 2023, Номер 186(18), С. 3882 - 3902.e24

Опубликована: Авг. 1, 2023

Язык: Английский

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Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion

Nature, Год журнала: 2023, Номер 615(7952), С. 472 - 481

Опубликована: Март 1, 2023

Язык: Английский

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Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 18, 2023

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell transcriptomic analysis HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in core (TC) leading edge (LE) transcriptional architectures. We show that TC LE are characterized by unique profiles, neighboring cellular compositions, ligand-receptor interactions. demonstrate gene expression profile associated with is conserved across different cancers while tissue specific, highlighting common mechanisms underlying progression invasion. Additionally, find our signature worse clinical outcomes improved prognosis multiple cancer types. Finally, using silico modeling approach, describe spatially-regulated patterns development OSCC predictably drug Our work provides pan-cancer insights into interactive atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) can be foundational for developing novel targeted therapies.

Язык: Английский

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Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer

Cell, Год журнала: 2022, Номер 185(25), С. 4717 - 4736.e25

Опубликована: Дек. 1, 2022

Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler (velvet) regenerate, whereas back forms scar. Single-cell multi-omics reveal uninjured velvet fibroblasts resemble human fetal fibroblasts, express inflammatory mediators mimicking pro-fibrotic adult and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: amplify myeloid infiltration maturation during repair, adopt an immunosuppressive phenotype restricts leukocyte recruitment hastens resolution. Ectopic transplantation to scar-forming is initially regenerative, but progressively transitions a akin the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration diminished intensifying, or enhanced neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent powerful comparative model for interrogating divergent wound healing outcomes, our results nominate decoupling interactions as promising approach mitigate

Язык: Английский

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