RESUMEN
Immune cells are characterized by diversity, specificity, plasticity, and adaptability-properties that enable them to contribute to homeostasis and respond specifically and dynamically to the many threats encountered by the body. Single-cell technologies, including the assessment of transcriptomics, genomics, and proteomics at the level of individual cells, are ideally suited to studying these properties of immune cells. In this review we discuss the benefits of adopting single-cell approaches in studying underappreciated qualities of immune cells and highlight examples where these technologies have been critical to advancing our understanding of the immune system in health and disease.
Asunto(s)
Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad , Análisis de la Célula Individual , Animales , Biomarcadores , Susceptibilidad a Enfermedades , Homeostasis , Humanos , Sistema Inmunológico/citología , Imagen Molecular , Análisis de la Célula Individual/métodosRESUMEN
Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here, we present CellHint, a predictive clustering tree-based tool to resolve cell-type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with â¼3.7 million cells and various machine learning models for automatic cell annotation across human tissues.
Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Humanos , Bases de Datos Factuales , Análisis de la Célula IndividualRESUMEN
We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5-22 post-conception weeks. We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models.
Asunto(s)
Feto , Pulmón , Humanos , Diferenciación Celular , Perfilación de la Expresión Génica , Pulmón/citología , Organogénesis , Organoides , Atlas como Asunto , Feto/citologíaRESUMEN
The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.
Asunto(s)
Células Asesinas Naturales , Linfocitos Infiltrantes de Tumor , Neoplasias , Transcriptoma , Microambiente Tumoral , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Microambiente Tumoral/inmunología , Neoplasias/inmunología , Neoplasias/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Perfilación de la Expresión Génica , Análisis de la Célula Individual , Redes Reguladoras de Genes , Antígeno CD56/metabolismo , Regulación Neoplásica de la Expresión Génica , Diferenciación CelularRESUMEN
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.
Asunto(s)
Células Enteroendocrinas/metabolismo , ARN Mensajero/genética , Células Cultivadas , Hormonas Gastrointestinales/genética , Tracto Gastrointestinal/metabolismo , Péptido 1 Similar al Glucagón/genética , Humanos , Organoides/metabolismo , Factores de Transcripción/genética , Transcriptoma/genéticaRESUMEN
T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, autoimmunity, and tumor immunology. Using a newly developed, genome-wide retroviral CRISPR knockout (KO) library, combined with RNA-seq, ATAC-seq, and ChIP-seq, we have dissected the regulatory circuitry governing activation and differentiation of these cells. Our experiments distinguish cell activation versus differentiation in a quantitative framework. We demonstrate that these two processes are tightly coupled and are jointly controlled by many transcription factors, metabolic genes, and cytokine/receptor pairs. There are only a small number of genes regulating differentiation without any role in activation. By combining biochemical and genetic data, we provide an atlas for Th2 differentiation, validating known regulators and identifying factors, such as Pparg and Bhlhe40, as part of the core regulatory network governing Th2 helper cell fates.
Asunto(s)
Receptor Cross-Talk/inmunología , Células Th2/inmunología , Células Th2/metabolismo , Animales , Sistemas CRISPR-Cas/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Memoria Inmunológica , Malaria/inmunología , Plasmodium/inmunología , Transcriptoma , Traslado Adoptivo , Animales , Antimaláricos/farmacología , Biomarcadores , Cromatina/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Malaria/parasitología , Malaria/terapia , Ratones , Plasmodium/efectos de los fármacosRESUMEN
Gastrointestinal microbiota and immune cells interact closely and display regional specificity; however, little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterization of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady state. We describe distinct helper T cell activation and migration profiles along the colon and characterize the transcriptional adaptation trajectory of regulatory T cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from the cecum to the sigmoid colon and link this to the increasing number of reactive bacterial species.
Asunto(s)
Colon/inmunología , Colon/microbiología , Microbioma Gastrointestinal/inmunología , Adulto , Linfocitos B/inmunología , Colon/citología , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Especificidad de Órganos , RNA-Seq , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , TranscriptomaRESUMEN
The assembly of individual proteins into functional complexes is fundamental to nearly all biological processes. In recent decades, many thousands of homomeric and heteromeric protein complex structures have been determined, greatly improving our understanding of the fundamental principles that control symmetric and asymmetric quaternary structure organization. Furthermore, our conception of protein complexes has moved beyond static representations to include dynamic aspects of quaternary structure, including conformational changes upon binding, multistep ordered assembly pathways, and structural fluctuations occurring within fully assembled complexes. Finally, major advances have been made in our understanding of protein complex evolution, both in reconstructing evolutionary histories of specific complexes and in elucidating general mechanisms that explain how quaternary structure tends to evolve. The evolution of quaternary structure occurs via changes in self-assembly state or through the gain or loss of protein subunits, and these processes can be driven by both adaptive and nonadaptive influences.
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Proteínas/química , Proteínas/metabolismo , Archaea/química , Bacterias/química , Cristalografía por Rayos X , Eucariontes/química , Evolución Molecular , Humanos , Complejos Multiproteicos/química , Dominios y Motivos de Interacción de Proteínas , Mapas de Interacción de Proteínas , Estructura Cuaternaria de ProteínaRESUMEN
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Asunto(s)
Mucosa Intestinal , Membrana Mucosa , Linfocitos T Reguladores , Animales , Femenino , Masculino , Ratones , Antígenos CD/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Helicobacter hepaticus/inmunología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Cadenas alfa de Integrinas/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Análisis de Expresión Génica de una Sola Célula , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/citología , TranscriptomaRESUMEN
The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.
Asunto(s)
COVID-19 , Nasofaringe , SARS-CoV-2 , Análisis de la Célula Individual , Linfocitos T , Humanos , COVID-19/inmunología , COVID-19/virología , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/fisiología , Nasofaringe/virología , Nasofaringe/inmunología , Linfocitos T/inmunología , Linfocitos T/virología , Interferones/inmunología , Interferones/metabolismo , Masculino , Femenino , Macrófagos/inmunología , Macrófagos/virología , Replicación Viral , Células Epiteliales/virología , Células Epiteliales/inmunología , Factores de Tiempo , AdultoRESUMEN
During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone-marrow-derived hematopoietic progenitors that migrate through the bloodstream. The current understanding of the nature of thymic immigrants is largely based on data from pre-clinical models. Here, we employed single-cell RNA sequencing (scRNA-seq) to examine the immature postnatal thymocyte population in humans. Integration of bone marrow and peripheral blood precursor datasets identified two putative thymus seeding progenitors that varied in expression of CD7; CD10; and the homing receptors CCR7, CCR9, and ITGB7. Whereas both precursors supported T cell development, only one contributed to intrathymic dendritic cell (DC) differentiation, predominantly of plasmacytoid dendritic cells. Trajectory inference delineated the transcriptional dynamics underlying early human T lineage development, enabling prediction of transcription factor (TF) modules that drive stage-specific steps of human T cell development. This comprehensive dataset defines the expression signature of immature human thymocytes and provides a resource for the further study of human thymopoiesis.
Asunto(s)
Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , ARN Citoplasmático Pequeño/genética , Timocitos/citología , Timocitos/metabolismo , Biomarcadores , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Análisis de la Célula Individual , Timocitos/inmunología , TranscriptomaRESUMEN
The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.
Asunto(s)
Multiómica , Primer Trimestre del Embarazo , Trofoblastos , Femenino , Humanos , Embarazo , Movimiento Celular , Placenta/irrigación sanguínea , Placenta/citología , Placenta/fisiología , Primer Trimestre del Embarazo/fisiología , Trofoblastos/citología , Trofoblastos/metabolismo , Trofoblastos/fisiología , Decidua/irrigación sanguínea , Decidua/citología , Relaciones Materno-Fetales/fisiología , Análisis de la Célula Individual , Miometrio/citología , Miometrio/fisiología , Diferenciación Celular , Organoides/citología , Organoides/fisiología , Células Madre/citología , Transcriptoma , Factores de Transcripción/metabolismo , Comunicación CelularRESUMEN
Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.
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/metabolismoRESUMEN
Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.
Asunto(s)
Adaptación Fisiológica/inmunología , Análisis de la Célula Individual/métodos , Linfocitos T Reguladores/inmunología , Transcriptoma/inmunología , Adaptación Fisiológica/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/inmunología , Colon/inmunología , Colon/metabolismo , Humanos , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Piel/inmunología , Piel/metabolismo , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. ILCs arise from lymphoid progenitors undergoing lineage restriction and the development of specialized ILC subsets. We generated "5x polychromILC" transcription factor reporter mice to delineate ILC precursor states by revealing the multifaceted expression of key ILC-associated transcription factors (Id2, Bcl11b, Gata3, RORγt, and RORα) during ILC development in the bone marrow. This approach allowed previously unattained enrichment of rare progenitor subsets and revealed hitherto unappreciated ILC precursor heterogeneity. In vivo and in vitro assays identified precursors with potential to generate all ILC subsets and natural killer (NK) cells, and also permitted discrimination of elusive ILC3 bone marrow antecedents. Single-cell gene expression analysis identified a discrete ILC2-committed population and delineated transition states between early progenitors and a highly heterogeneous ILC1, ILC3, and NK precursor cell cluster. This diversity might facilitate greater lineage potential upon progenitor recruitment to peripheral tissues.
Asunto(s)
Médula Ósea/inmunología , Subgrupos Linfocitarios/fisiología , Linfocitos/fisiología , Células Progenitoras Linfoides/fisiología , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Línea Celular , Linaje de la Célula , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Inmunidad Innata , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Análisis de la Célula Individual , Factores de Transcripción/genéticaRESUMEN
The development of single-cell and spatial transcriptomics methods was instrumental in the conception of the Human Cell Atlas initiative, which aims to generate an integrated map of all cells across the human body. These technology advances are bringing increasing depth and resolution to maps of human organs and tissues, as well as our understanding of individual human cell types. Commonalities as well as tissue-specific features of primary and supportive cell types across human organs are beginning to emerge from these human tissue maps. In this Review, we highlight key biological insights obtained from cross-tissue studies into epithelial, fibroblast, vascular and immune cells based on single-cell gene expression data in humans and contrast it with mechanisms reported in mice.
Asunto(s)
Análisis de la Célula Individual , Transcriptoma , Animales , Humanos , RatonesRESUMEN
Is the order in which proteins assemble into complexes important for biological function? Here, we seek to address this by searching for evidence of evolutionary selection for ordered protein complex assembly. First, we experimentally characterize the assembly pathways of several heteromeric complexes and show that they can be simply predicted from their three-dimensional structures. Then, by mapping gene fusion events identified from fully sequenced genomes onto protein complex assembly pathways, we demonstrate evolutionary selection for conservation of assembly order. Furthermore, using structural and high-throughput interaction data, we show that fusion tends to optimize assembly by simplifying protein complex topologies. Finally, we observe protein structural constraints on the gene order of fusion that impact the potential for fusion to affect assembly. Together, these results reveal the intimate relationships among protein assembly, quaternary structure, and evolution and demonstrate on a genome-wide scale the biological importance of ordered assembly pathways.