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2.
Front Physiol ; 15: 1425620, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39318362

RESUMO

The innermost layer of the vessel wall is constantly subjected to recurring and relenting mechanical forces by virtue of their direct contact with blood flow. Endothelial cells of the vessel are exposed to distension, pressure, and shear stress; adaptation to these hemodynamic forces requires significant remodeling of the cytoskeleton which includes changes in actin, intermediate filaments, and microtubules. While much is known about the effect of shear stress on the endothelial actin cytoskeleton; the impact of hemodynamic forces on the microtubule network has not been investigated in depth. Here we used imaging techniques and protein expression analysis to characterize how pharmacological and genetic perturbations of microtubule properties alter endothelial responses to laminar shear stress. Our findings revealed that pharmacological suppression of microtubule dynamics blocked two typical responses to laminar shear stress: endothelial elongation and alignment. The findings demonstrate the essential contribution of the microtubule network to changes in cell shape driven by mechanical forces. Furthermore, we observed a flow-dependent increase in microtubule acetylation that occurred early in the process of cell elongation. Pharmacological manipulation of microtubule acetylation showed a direct and causal relationship between acetylation and endothelial elongation. Finally, genetic inactivation of aTAT1, a microtubule acetylase, led to significant loss of acetylation as well as inhibition of cell elongation in response to flow. In contrast, loss of HDAC6, a microtubule deacetylase, resulted in robust microtubule acetylation with cells displaying faster kinetics of elongation and alignment. Taken together, our findings uncovered the critical contributions of HDAC6 and aTAT1, that through their roles in the regulation of microtubule acetylation, are key mediators of endothelial mechanotransduction.

4.
J Clin Invest ; 134(2)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38015629

RESUMO

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.


Assuntos
Encéfalo , Demência Vascular , Receptor Notch3 , Animais , Humanos , Camundongos , Encéfalo/metabolismo , CADASIL/genética , CADASIL/patologia , Demência Vascular/metabolismo , Camundongos Knockout , Mutação , Receptor Notch3/genética
5.
Cell Rep ; 43(1): 113627, 2024 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-38157296

RESUMO

Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.


Assuntos
Proteínas de Membrana , Fator A de Crescimento do Endotélio Vascular , Animais , Camundongos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células , Células Endoteliais/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica , Receptores Notch/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Nat Cardiovasc Res ; 2: 2023530-549, 2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37745941

RESUMO

The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity.

7.
Curr Opin Cell Biol ; 85: 102232, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37703647

RESUMO

Physical forces exert profound effects on cells affecting fate, function, and response to stressors. In the case of the endothelium, the layer that resides in the inner surface of blood vessels, the collective effect of hemodynamic forces influences the onset and severity of vascular pathologies. Justifiably, much emphasis has been placed in understanding how endothelial cells sense and respond to mechanical challenges, particularly hemodynamic shear stress. In this review, we highlight recent developments that have expanded our understanding of the molecular mechanisms underlying mechanotransduction. We describe examples of protein compartmentalization in response to shear stress, consider the contribution of the glycocalyx, and discuss the specific role ion channels in response to flow. We also highlight the recently recognized contribution of the receptor ALK5 in sensing turbulent flow. Research in the last three years has enriched our understanding of the molecular landscape responsible for recognizing and transducing shear stress responses, including novel transcriptional-dependent and transcriptional-independent mechanisms.


Assuntos
Células Endoteliais , Mecanotransdução Celular , Mecanotransdução Celular/fisiologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Estresse Mecânico
8.
J Clin Invest ; 133(10)2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-37183820

RESUMO

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-ß signaling. Deleting TGF-ß receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.


Assuntos
Infarto do Miocárdio , Pericitos , Camundongos , Animais , Pericitos/metabolismo , Infarto do Miocárdio/metabolismo , Coração , Fibrose , Matriz Extracelular/metabolismo , Remodelação Ventricular/genética , Miocárdio/metabolismo
9.
Cell Rep ; 42(5): 112411, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37086408

RESUMO

Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.


Assuntos
Proteínas de Ligação a RNA , Transdução de Sinais , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estabilidade de RNA/genética , Tristetraprolina/genética , Tristetraprolina/metabolismo
10.
Elife ; 122023 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-36971339

RESUMO

Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA sequencing and protein expression by liquid chromatography-mass spectrometry directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.


Assuntos
Células Endoteliais , Perfilação da Expressão Gênica , Humanos , Células Endoteliais/metabolismo , Endotélio , Células Cultivadas , Técnicas de Cocultura
11.
EMBO Mol Med ; 15(5): e17520, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36975378

RESUMO

Retinopathy is one of the more severe complications associated with diabetes. Targeting vascular pathology has shown benefits, but current therapies are costly and have limitations. In this issue of EMBO Molecular Medicine, Niaudet et al report that the activation of the S1PR1 receptor in endothelial cells is able to block abnormal permeability, neovascular tuft development, and resolve pathological vascular lesions associated with hypoxia-driven retinopathy.


Assuntos
Diabetes Mellitus Experimental , Doenças Retinianas , Animais , Humanos , Células Endoteliais/patologia , Doenças Retinianas/patologia , Hipóxia , Lipídeos
12.
FASEB J ; 36(12): e22639, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36322029

RESUMO

Exposure of biological systems to acute or chronic insults triggers a host of molecular and physiological responses to either tolerate, adapt, or fully restore homeostasis; these responses constitute the hallmarks of resilience. Given the many facets, dimensions, and discipline-specific focus, gaining a shared understanding of "resilience" has been identified as a priority for supporting advances in cardiovascular health. This report is based on the working definition: "Resilience is the ability of living systems to successfully maintain or return to homeostasis in response to physical, molecular, individual, social, societal, or environmental stressors or challenges," developed after considering many factors contributing to cardiovascular resilience through deliberations of multidisciplinary experts convened by the National Heart, Lung, and Blood Institute during a workshop entitled: "Enhancing Resilience for Cardiovascular Health and Wellness." Some of the main emerging themes that support the possibility of enhancing resilience for cardiovascular health include optimal energy management and substrate diversity, a robust immune system that safeguards tissue homeostasis, and social and community support. The report also highlights existing research challenges, along with immediate and long-term opportunities for resilience research. Certain immediate opportunities identified are based on leveraging existing high-dimensional data from longitudinal clinical studies to identify vascular resilience measures, create a 'resilience index,' and adopt a life-course approach. Long-term opportunities include developing quantitative cell/organ/system/community models to identify resilience factors and mechanisms at these various levels, designing experimental and clinical interventions that specifically assess resilience, adopting global sharing of resilience-related data, and cross-domain training of next-generation researchers in this field.


Assuntos
National Heart, Lung, and Blood Institute (U.S.) , Pesquisadores , Estados Unidos , Humanos
13.
Cell Rep ; 41(3): 111511, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36261010

RESUMO

Glioblastoma (GBM) is characterized by extensive microvascular hyperproliferation. In addition to supplying blood to the tumor, GBM vessels also provide trophic support to glioma cells and serve as conduits for migration into the surrounding brain, promoting recurrence. Here, we enrich CD31-expressing glioma vascular cells (GVCs) and A2B5-expressing glioma tumor cells (GTCs) from primary GBM and use RNA sequencing to create a comprehensive molecular interaction map of the secreted and extracellular factors elaborated by GVCs that can interact with receptors and membrane molecules on GTCs. To validate our findings, we utilize functional assays, including a hydrogel-based migration assay and in vivo mouse models to demonstrate that one identified factor, the little-studied integrin binding sialoprotein (IBSP), enhances tumor growth and promotes the migration of GTCs along the vasculature. This perivascular niche interactome will serve as a resource to the research community in defining the potential functions of the GBM vasculature.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Animais , Camundongos , Glioblastoma/patologia , Sialoproteína de Ligação à Integrina/metabolismo , Neoplasias Encefálicas/patologia , Células-Tronco Neoplásicas/metabolismo , Glioma/patologia , Movimento Celular , Hidrogéis
14.
Front Cell Dev Biol ; 10: 905927, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35784481

RESUMO

Vascular cells are constantly subjected to physical forces associated with the rhythmic activities of the heart, which combined with the individual geometry of vessels further imposes oscillatory, turbulent, or laminar shear stresses on vascular cells. These hemodynamic forces play an important role in regulating the transcriptional program and phenotype of endothelial and smooth muscle cells in different regions of the vascular tree. Within the aorta, the lesser curvature of the arch is characterized by disturbed, oscillatory flow. There, endothelial cells become activated, adopting pro-inflammatory and athero-prone phenotypes. This contrasts the descending aorta where flow is laminar and endothelial cells maintain a quiescent and atheroprotective phenotype. While still unclear, the specific mechanisms involved in mechanosensing flow patterns and their molecular mechanotransduction directly impact the nucleus with consequences to transcriptional and epigenetic states. The linker of nucleoskeleton and cytoskeleton (LINC) protein complex transmits both internal and external forces, including shear stress, through the cytoskeleton to the nucleus. These forces can ultimately lead to changes in nuclear integrity, chromatin organization, and gene expression that significantly impact emergence of pathology such as the high incidence of atherosclerosis in progeria. Therefore, there is strong motivation to understand how endothelial nuclei can sense and respond to physical signals and how abnormal responses to mechanical cues can lead to disease. Here, we review the evidence for a critical role of the nucleus as a mechanosensor and the importance of maintaining nuclear integrity in response to continuous biophysical forces, specifically shear stress, for proper vascular function and stability.

15.
Nat Cardiovasc Res ; 1(1): 67-84, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35599984

RESUMO

Leukocytes and endothelial cells frequently cooperate to resolve inflammatory events. In most cases, these interactions are transient in nature and triggered by immunological insults. Here, we report that in areas of disturbed blood flow, aortic endothelial cells permanently and intimately associate with a population of specialized macrophages that are recruited at birth from the closing ductus arteriosus and share the luminal surface with the endothelium becoming interwoven in the tunica intima. Anatomical changes that affect hemodynamics, like in patent ductus arteriosus, alter macrophage seeding to coincide with regions of disturbed flow. Aortic resident macrophages expand in situ via direct cell renewal. Induced-depletion of intimal macrophages led to thrombin-mediated endothelial cell contraction, progressive fibrin accumulation and formation of microthrombi that, once dislodged, caused blockade of vessels in several organs. Together the findings revealed that intravascular resident macrophages are essential to regulate thrombin activity and clear fibrin deposits in regions of disturbed blood flow.

16.
Arterioscler Thromb Vasc Biol ; 42(7): 831-838, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35510549

RESUMO

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.


Assuntos
Disfunção Cognitiva , Demência Vascular , Animais , Cognição , Disfunção Cognitiva/genética , Demência Vascular/genética , Camundongos , Fenótipo , Reprodutibilidade dos Testes
17.
Arterioscler Thromb Vasc Biol ; 42(6): 732-742, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35443793

RESUMO

OBJECTIVE: Failure to close the ductus arteriosus, patent ductus arteriosus, accounts for 10% of all congenital heart defects. Despite significant advances in patent ductus arteriosus management, including pharmacological treatment targeting the prostaglandin pathway, a proportion of patients fail to respond and must undergo surgical intervention. Thus, further refinement of the cellular and molecular mechanisms that govern vascular remodeling of this vessel is required. METHODS: We performed single-cell RNA-sequencing of the ductus arteriosus in mouse embryos at E18.5 (embryonic day 18.5), and P0.5 (postnatal day 0.5), and P5 to identify transcriptional alterations that might be associated with remodeling. We further confirmed our findings using transgenic mouse models coupled with immunohistochemistry analysis. RESULTS: The intermediate filament vimentin emerged as a candidate that might contribute to closure of the ductus arteriosus. Indeed, mice with genetic deletion of vimentin fail to complete vascular remodeling of the ductus arteriosus. To seek mechanisms, we turned to the RNA-sequencing data that indicated changes in Jagged1 with similar profile to vimentin and pointed to potential links with Notch. In fact, Notch3 signaling was impaired in vimentin null mice and vimentin null mice phenocopies patent ductus arteriosus in Jagged1 endothelial and smooth muscle deleted mice. CONCLUSIONS: Through single-cell RNA-sequencing and by tracking closure of the ductus arteriosus in mice, we uncovered the unexpected contribution of vimentin in driving complete closure of the ductus arteriosus through a mechanism that includes deregulation of the Notch signaling pathway.


Assuntos
Permeabilidade do Canal Arterial , Canal Arterial , Animais , Canal Arterial/metabolismo , Permeabilidade do Canal Arterial/genética , Permeabilidade do Canal Arterial/metabolismo , Humanos , Filamentos Intermediários/metabolismo , Camundongos , RNA , Remodelação Vascular , Vimentina/genética , Vimentina/metabolismo
18.
Nature ; 604(7906): 534-540, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35418685

RESUMO

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ haemogenic endothelial cells, which arose from an IL33+ALDH1A1+ arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta-gonad-mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.


Assuntos
Células Endoteliais , Células-Tronco Hematopoéticas , Diferenciação Celular , Endotélio , Feminino , Hematopoese , Humanos , Mesonefro , Gravidez
20.
Nat Immunol ; 22(7): 839-850, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34168371

RESUMO

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.


Assuntos
Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Mycobacterium leprae/imunologia , Pele/imunologia , Adolescente , Adulto , Idoso , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/patologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Queratinócitos/patologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/microbiologia , Hanseníase Virchowiana/patologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/microbiologia , Hanseníase Tuberculoide/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , RNA-Seq , Análise de Célula Única , Pele/microbiologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Transcriptoma
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