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1.
Commun Biol ; 4(1): 1186, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650224

RESUMO

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.

2.
Nature ; 597(7875): 250-255, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497389

RESUMO

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.


Assuntos
Envelhecimento , Sistema Nervoso Entérico/citologia , Feto/citologia , Saúde , Intestinos/citologia , Intestinos/crescimento & desenvolvimento , Linfonodos/citologia , Linfonodos/crescimento & desenvolvimento , Adulto , Animais , Criança , Doença de Crohn/patologia , Conjuntos de Dados como Assunto , Sistema Nervoso Entérico/anatomia & histologia , Sistema Nervoso Entérico/embriologia , Sistema Nervoso Entérico/crescimento & desenvolvimento , Células Epiteliais/citologia , Feminino , Feto/anatomia & histologia , Feto/embriologia , Humanos , Intestinos/embriologia , Intestinos/inervação , Linfonodos/embriologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Receptores de IgG/metabolismo , Transdução de Sinais , Análise Espaço-Temporal , Fatores de Tempo
3.
Science ; 373(6556): 760-767, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34385390

RESUMO

The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett's esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett's esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett's esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.


Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Cárdia/citologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Esôfago de Barrett/genética , Esôfago de Barrett/metabolismo , Cárdia/química , Diferenciação Celular , Linhagem da Célula , Transformação Celular Neoplásica , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Esôfago/citologia , Esôfago/metabolismo , Glândulas Exócrinas/química , Glândulas Exócrinas/citologia , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Queratina-7/análise , Metaplasia , Fenótipo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA-Seq , Análise de Célula Única , Transcrição Genética , Transcriptoma
4.
Commun Biol ; 4(1): 798, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172826

RESUMO

The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Medicina Regenerativa , Engenharia Genética , Rejeição de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Tolerância Imunológica , Imunidade Inata , Ativação Linfocitária , Transplante de Células-Tronco , Linfócitos T/imunologia
5.
Sci Rep ; 11(1): 10418, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001961

RESUMO

Cryopreservation offers the potential to increase the availability of pancreatic islets for treatment of diabetic patients. However, current protocols, which use dimethyl sulfoxide (DMSO), lead to poor cryosurvival of islets. We demonstrate that equilibration of mouse islets with small molecules in aqueous solutions can be accelerated from > 24 to 6 h by increasing incubation temperature to 37 °C. We utilize this finding to demonstrate that current viability staining protocols are inaccurate and to develop a novel cryopreservation method combining DMSO with trehalose pre-incubation to achieve improved cryosurvival. This protocol resulted in improved ATP/ADP ratios and peptide secretion from ß-cells, preserved cAMP response, and a gene expression profile consistent with improved cryoprotection. Our findings have potential to increase the availability of islets for transplantation and to inform the design of cryopreservation protocols for other multicellular aggregates, including organoids and bioengineered tissues.

6.
Cancer Immunol Immunother ; 70(10): 2737-2750, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33830275

RESUMO

Despite the significant contributions of immunocompetent mouse models to the development and assessment of cancer immunotherapies, they inadequately represent the genetic and biological complexity of corresponding human cancers. Immunocompromised mice reconstituted with a human immune system (HIS) and engrafted with patient-derived tumor xenografts are a promising novel preclinical model for the study of human tumor-immune interactions. Whilst overcoming limitations of immunocompetent models, HIS-tumor models often rely on reconstitution with allogeneic immune cells, making it difficult to distinguish between anti-tumor and alloantigen responses. Models that comprise of autologous human tumor and human immune cells provide a platform that is more representative of the patient immune-tumor interaction. However, limited access to autologous tissues, short experimental windows, and poor retention of tumor microenvironment and tumor infiltrating lymphocyte components are major challenges affecting the establishment and application of autologous models. This review outlines existing preclinical murine models for the study of immuno-oncology, and highlights innovations that can be applied to improve the feasibility and efficacy of autologous models.


Assuntos
Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Medição de Risco
7.
Nature ; 593(7859): 405-410, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33911282

RESUMO

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.


Assuntos
Células Sanguíneas/metabolismo , Diferenciação Celular/genética , Análise Mutacional de DNA/métodos , Músculo Liso/metabolismo , Mutação , Neurônios/metabolismo , Imagem Individual de Molécula/métodos , Células-Tronco/metabolismo , Doença de Alzheimer/genética , Células Sanguíneas/citologia , Divisão Celular , Estudos de Coortes , Colo/citologia , Epitélio/metabolismo , Granulócitos/citologia , Granulócitos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/citologia , Mutagênese , Taxa de Mutação , Neurônios/citologia , Células-Tronco/citologia
9.
Science ; 371(6531): 839-846, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33602855

RESUMO

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium.


Assuntos
Doenças dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/fisiologia , Ductos Biliares/citologia , Terapia Baseada em Transplante de Células e Tecidos , Células Epiteliais/citologia , Organoides/transplante , Animais , Bile , Ductos Biliares/fisiologia , Ductos Biliares Intra-Hepáticos/citologia , Ducto Colédoco/citologia , Células Epiteliais/fisiologia , Vesícula Biliar/citologia , Regulação da Expressão Gênica , Humanos , Fígado/fisiologia , Transplante de Fígado , Transplante de Células-Tronco Mesenquimais , Camundongos , Organoides/fisiologia , RNA-Seq , Obtenção de Tecidos e Órgãos , Transcriptoma
10.
Hepatology ; 73(1): 247-267, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222998

RESUMO

BACKGROUND AND AIMS: Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. APPROACH AND RESULTS: Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions. CONCLUSIONS: Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.


Assuntos
Ductos Biliares Extra-Hepáticos/citologia , Ductos Biliares Intra-Hepáticos/citologia , Células Epiteliais/citologia , Organoides/fisiologia , Animais , Bile , Ductos Biliares Extra-Hepáticos/fisiologia , Ductos Biliares Intra-Hepáticos/fisiologia , Diferenciação Celular , Ducto Colédoco/citologia , Células Epiteliais/fisiologia , Vesícula Biliar/citologia , Regulação da Expressão Gênica , Humanos , Queratina-19/análise , Fígado/fisiologia , Camundongos , RNA-Seq , Obtenção de Tecidos e Órgãos
11.
Liver Transpl ; 27(2): 264-280, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33222385

RESUMO

Liver transplantation (LT) is considered the gold standard of curative treatment for patients with end-stage liver disease or nonresectable hepatic malignant tumors. Rejection after LT is the main nontechnical factor affecting the prognosis of recipients. Medical and surgical advances, combined with improved immunosuppression with drugs such as calcineurin inhibitors (CNIs), have contributed to an increase in 1-year graft survival to around 80%. However, medium- and long-term improvements in LT outcomes have lagged behind. Importantly, CNIs and other classical immunosuppressive drugs are associated with significant adverse effects, including malignancies, cardiovascular disease, and severe renal dysfunction. Immunomodulation using regulatory T cells (Tregs) is emerging as a promising alternative to classical immunosuppression. Since their discovery, the immunomodulatory effects of Tregs have been demonstrated in a range of diseases. This has rejuvenated the interest in using Tregs as a therapeutic strategy to induce immune tolerance after LT. In this review, we first summarize the discovery and development of Tregs. We then review the preclinical data supporting their production, mechanism of action, and therapeutic efficacy followed by a summary of relevant clinical trials. Finally, we discuss the outstanding challenges of Treg therapy and its future prospects for routine use in LT.


Assuntos
Transplante de Fígado , Linfócitos T Reguladores , Inibidores de Calcineurina , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressão , Imunossupressores/uso terapêutico , Transplante de Fígado/efeitos adversos
12.
Cancer Discov ; 11(2): 340-361, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33087317

RESUMO

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. SIGNIFICANCE: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211.

13.
Cardiovasc Res ; 117(4): 1188-1201, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32766828

RESUMO

AIMS : Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS : To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION : Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.

14.
Trends Mol Med ; 27(2): 185-198, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32952044

RESUMO

Advances in surgical procedures, technology, and immune suppression have transformed organ transplantation. However, the metabolic changes that occur during organ retrieval, storage, and implantation have been relatively neglected since the developments many decades ago of cold storage organ preservation solutions. In this review we discuss how the metabolic changes that occur within the organ during transplantation, particularly those associated with mitochondria, may contribute to the outcome. We show how a better understanding of these processes can lead to changes in surgical practice and the development of new drug classes to improve the function and longevity of transplanted grafts, while increasing the pool of organs available for transplantation.

15.
Cell Stem Cell ; 27(6): 905-919.e10, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33142113

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term, three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and proinflammatory genes in infected hAT2 cells, indicating a robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2 and the application of defined 3D hAT2 cultures as models for respiratory diseases.


Assuntos
COVID-19 , Alvéolos Pulmonares/virologia , SARS-CoV-2/fisiologia , Células-Tronco/virologia , COVID-19/virologia , Técnicas de Cultura de Células , Meios de Cultura , Humanos , Interferons/metabolismo , Modelos Biológicos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/ultraestrutura , SARS-CoV-2/ultraestrutura , Transcriptoma , Internalização do Vírus , Replicação Viral
16.
Clin Transl Immunology ; 9(11): e1202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173582

RESUMO

Objectives: Humanised mice have emerged as valuable models for pre-clinical testing of the safety and efficacy of immunotherapies. Given the variety of models available, selection of the most appropriate humanised mouse model is critical in study design. Here, we aimed to develop a model for predicting cytokine release syndrome (CRS) while minimising graft-versus-host disease (GvHD). Methods: To overcome donor-induced variation, we directly compared the in vitro and in vivo immune phenotype of immunodeficient NSG mice reconstituted with human bone marrow (BM) CD34+ haematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs) or spleen mononuclear cells (SPMCs) from the same human donors. SPMC engraftment in NSG-dKO mice, which lack MHC class I and II, was also evaluated as a strategy to limit GvHD. Another group of mice was engrafted with umbilical cord blood (UCB) CD34+ HSCs. Induction of CRS in vivo was investigated upon administration of the anti-CD3 monoclonal antibody OKT3. Results: PBMC- and SPMC-reconstituted NSG mice showed short-term survival, with engrafted human T cells exhibiting mostly an effector memory phenotype. Survival in SPMC-reconstituted NSG-dKO mice was significantly longer. Conversely, both BM and UCB-HSC models showed longer survival, without demonstrable GvHD and a more naïve T-cell phenotype. PBMC- and SPMC-reconstituted mice, but not BM-HSC or UCB-HSC mice, experienced severe clinical signs of CRS upon administration of OKT3. Conclusion: PBMC- and SPMC-reconstituted NSG mice better predict OKT3-mediated CRS. The SPMC model allows generation of large experimental groups, and the use of NSG-dKO mice mitigates the limitation of early GvHD.

17.
Science ; 370(6512): 75-82, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004514

RESUMO

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.


Assuntos
Genes Neoplásicos , Mutagênese , Seleção Genética , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/patologia , Urotélio/patologia , Desaminases APOBEC/genética , Adulto , Idoso , Biópsia , Montagem e Desmontagem da Cromatina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênicos/análise , Mutação
18.
Commun Biol ; 3(1): 577, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067560

RESUMO

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.


Assuntos
Estimulação Elétrica , Baço/inervação , Animais , Estimulação Elétrica/métodos , Terapia por Estimulação Elétrica/métodos , Fenômenos Eletrofisiológicos , Humanos , Baço/anatomia & histologia , Baço/irrigação sanguínea , Baço/citologia , Suínos
19.
Nature ; 588(7838): 466-472, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32971526

RESUMO

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.


Assuntos
Miocárdio/citologia , Análise de Célula Única , Transcriptoma , Adipócitos/classificação , Adipócitos/metabolismo , Adulto , Enzima de Conversão de Angiotensina 2/análise , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Células Epiteliais/classificação , Células Epiteliais/metabolismo , Epitélio , Feminino , Fibroblastos/classificação , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Átrios do Coração/anatomia & histologia , Átrios do Coração/citologia , Átrios do Coração/inervação , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/citologia , Ventrículos do Coração/inervação , Homeostase/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Miócitos Cardíacos/classificação , Miócitos Cardíacos/metabolismo , Neurônios/classificação , Neurônios/metabolismo , Pericitos/classificação , Pericitos/metabolismo , Receptores de Coronavírus/análise , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Células Estromais/classificação , Células Estromais/metabolismo
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