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1.
Nature ; 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39415002

RESUMEN

Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.

2.
Nature ; 619(7971): 801-810, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37438528

RESUMEN

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.


Asunto(s)
Microambiente Celular , Corazón , Multiómica , Miocardio , Humanos , Comunicación Celular , Fibroblastos/citología , Ácido Glutámico/metabolismo , Corazón/anatomía & histología , Corazón/inervación , Canales Iónicos/metabolismo , Miocardio/citología , Miocardio/inmunología , Miocardio/metabolismo , Miocitos Cardíacos/citología , Neuroglía/citología , Pericardio/citología , Pericardio/inmunología , Células Plasmáticas/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Nodo Sinoatrial/anatomía & histología , Nodo Sinoatrial/citología , Nodo Sinoatrial/fisiología , Sistema de Conducción Cardíaco/anatomía & histología , Sistema de Conducción Cardíaco/citología , Sistema de Conducción Cardíaco/metabolismo
3.
Nature ; 608(7922): 397-404, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35922511

RESUMEN

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.


Asunto(s)
Comunicación Celular , Sistema Inmunológico , Mapas de Interacción de Proteínas , Comunicación Celular/inmunología , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Leucocitos/química , Leucocitos/inmunología , Leucocitos/metabolismo , Unión Proteica , Proteoma/inmunología , Proteoma/metabolismo , Receptores de Superficie Celular/química , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo
4.
Nature ; 597(7875): 250-255, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34497389

RESUMEN

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.


Asunto(s)
Envejecimiento , Sistema Nervioso Entérico/citología , Feto/citología , Salud , Intestinos/citología , Intestinos/crecimiento & desarrollo , Ganglios Linfáticos/citología , Ganglios Linfáticos/crecimiento & desarrollo , Adulto , Animales , Niño , Enfermedad de Crohn/patología , Conjuntos de Datos como Asunto , Sistema Nervioso Entérico/anatomía & histología , Sistema Nervioso Entérico/embriología , Sistema Nervioso Entérico/crecimiento & desarrollo , Células Epiteliales/citología , Femenino , Feto/anatomía & histología , Feto/embriología , Humanos , Intestinos/embriología , Intestinos/inervación , Ganglios Linfáticos/embriología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos C57BL , Organogénesis , Receptores de IgG/metabolismo , Transducción de Señal , Análisis Espacio-Temporal , Factores de Tiempo
6.
Nat Genet ; 55(1): 66-77, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36543915

RESUMEN

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.


Asunto(s)
Pulmón , Mucosa Respiratoria , Humanos , Mucosa Respiratoria/metabolismo , Células Epiteliales/metabolismo , Linfocitos B , Inmunoglobulina A/metabolismo
7.
Science ; 376(6597): eabo0510, 2022 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-35549310

RESUMEN

Single-cell genomics studies have decoded the immune cell composition of several human prenatal organs but were limited in describing the developing immune system as a distributed network across tissues. We profiled nine prenatal tissues combining single-cell RNA sequencing, antigen-receptor sequencing, and spatial transcriptomics to reconstruct the developing human immune system. This revealed the late acquisition of immune-effector functions by myeloid and lymphoid cell subsets and the maturation of monocytes and T cells before peripheral tissue seeding. Moreover, we uncovered system-wide blood and immune cell development beyond primary hematopoietic organs, characterized human prenatal B1 cells, and shed light on the origin of unconventional T cells. Our atlas provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine, and disease understanding.


Asunto(s)
Sistema Inmunológico , Linfocitos , Monocitos , Genómica , Humanos , Sistema Inmunológico/embriología , Linfocitos/metabolismo , Monocitos/metabolismo , Especificidad de Órganos , RNA-Seq , Análisis de la Célula Individual
8.
Dev Cell ; 55(6): 771-783.e5, 2020 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-33290721

RESUMEN

Human gut development requires the orchestrated interaction of differentiating cell types. Here, we generate an in-depth single-cell map of the developing human intestine at 6-10 weeks post-conception. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells. We propose that these cells may contribute to differentiated cell subsets via the generation of LGR5-expressing stem cells and receive signals from surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNA-seq profiles from pediatric Crohn's disease epithelium alongside matched healthy controls to reveal disease-associated changes in the epithelial composition. Contrasting these with the fetal profiles reveals the re-activation of fetal transcription factors in Crohn's disease. Our study provides a resource available at www.gutcellatlas.org, and underscores the importance of unraveling fetal development in understanding disease.


Asunto(s)
Enfermedad de Crohn/genética , Mucosa Intestinal/metabolismo , Transcriptoma , Adolescente , Células Cultivadas , Niño , Enfermedad de Crohn/metabolismo , Humanos , Mucosa Intestinal/embriología , RNA-Seq , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Análisis de la Célula Individual , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
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