Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 148
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 186(7): 1478-1492.e15, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-36870331

RESUMEN

Lungs undergo mechanical strain during breathing, but how these biophysical forces affect cell fate and tissue homeostasis are unclear. We show that biophysical forces through normal respiratory motion actively maintain alveolar type 1 (AT1) cell identity and restrict these cells from reprogramming into AT2 cells in the adult lung. AT1 cell fate is maintained at homeostasis by Cdc42- and Ptk2-mediated actin remodeling and cytoskeletal strain, and inactivation of these pathways causes a rapid reprogramming into the AT2 cell fate. This plasticity induces chromatin reorganization and changes in nuclear lamina-chromatin interactions, which can discriminate AT1 and AT2 cell identity. Unloading the biophysical forces of breathing movements leads to AT1-AT2 cell reprogramming, revealing that normal respiration is essential to maintain alveolar epithelial cell fate. These data demonstrate the integral function of mechanotransduction in maintaining lung cell fate and identifies the AT1 cell as an important mechanosensor in the alveolar niche.


Asunto(s)
Células Epiteliales Alveolares , Mecanotransducción Celular , Células Epiteliales Alveolares/metabolismo , Células Cultivadas , Pulmón , Diferenciación Celular/fisiología , Respiración
2.
Cell ; 170(6): 1134-1148.e10, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28886382

RESUMEN

The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.


Asunto(s)
Pulmón/citología , Mesodermo/citología , Algoritmos , Animales , Células Epiteliales/metabolismo , Fibrosis/metabolismo , Perfilación de la Expresión Génica , Pulmón/patología , Pulmón/fisiología , Lesión Pulmonar/patología , Ratones , Organoides/citología , Comunicación Paracrina , Regeneración , Transducción de Señal , Análisis de la Célula Individual , Células Madre/metabolismo
3.
Cell ; 171(3): 573-587.e14, 2017 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-29033129

RESUMEN

Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.


Asunto(s)
Cromatina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Histona Desacetilasas/metabolismo , Lámina Nuclear/metabolismo , Células Madre/citología , Animales , Genoma , Ratones , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Células Madre/metabolismo
4.
Nature ; 604(7904): 120-126, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35355013

RESUMEN

The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.


Asunto(s)
Bronquiolos , Hurones , Células Madre Multipotentes , Alveolos Pulmonares , Animales , Bronquiolos/citología , Linaje de la Célula , Humanos , Pulmón/patología , Ratones , Células Madre Multipotentes/citología , Alveolos Pulmonares/citología , Enfermedad Pulmonar Obstructiva Crónica
5.
Circ Res ; 133(4): 353-365, 2023 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-37462036

RESUMEN

BACKGROUND: Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT. METHODS: Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [Ucp1]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq (RNA sequencing) was performed in BAT from WT and Ucp1-/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b. RESULTS: Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b-deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b-deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b-deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury. CONCLUSIONS: The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.


Asunto(s)
Enfermedad de la Arteria Coronaria , Factor 10 de Diferenciación de Crecimiento , Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Animales , Humanos , Ratones , Tejido Adiposo Pardo/metabolismo , Factor 10 de Diferenciación de Crecimiento/metabolismo , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Reperfusión
6.
Nature ; 575(7782): 375-379, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31618756

RESUMEN

Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy1. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM232. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.


Asunto(s)
Mitofagia , Animales , Línea Celular , Ratones , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Nucleótidos/metabolismo , Unión Proteica , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo
7.
Nature ; 573(7774): 430-433, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31511695

RESUMEN

Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.


Asunto(s)
Linfocitos T CD8-positivos , Fibrosis Endomiocárdica/terapia , Inmunoterapia Adoptiva , Animales , Antígenos de Superficie/inmunología , Linfocitos T CD8-positivos/inmunología , Fibrosis Endomiocárdica/inmunología , Fibroblastos/inmunología , Humanos , Masculino , Ratones , Ovalbúmina/inmunología , Cicatrización de Heridas
9.
Proc Natl Acad Sci U S A ; 119(43): e2123187119, 2022 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-36252035

RESUMEN

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.


Asunto(s)
Células Epiteliales Alveolares , Reprogramación Celular , Lesión Pulmonar , Proteínas de la Membrana , Proteínas Serina-Treonina Quinasas , Fibrosis Pulmonar , Células Epiteliales Alveolares/metabolismo , Estrés del Retículo Endoplásmico , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Inositol/metabolismo , Lesión Pulmonar/patología , Proteínas Serina-Treonina Quinasas/genética , Proteostasis , Fibrosis Pulmonar/genética , Proteínas de la Membrana/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismo
10.
Genes Dev ; 31(9): 889-903, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28546511

RESUMEN

A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We identified a feedback loop within the NANCI (Nkx2.1-associated noncoding intergenic RNA)-Nkx2.1 gene duplex that is essential for buffering Nkx2.1 expression, lung epithelial cell identity, and tissue homeostasis. Within this locus, Nkx2.1 directly inhibits NANCI, while NANCI acts in cis to promote Nkx2.1 transcription. Although loss of NANCI alone does not adversely affect lung development, concurrent heterozygous mutations in both NANCI and Nkx2.1 leads to persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate. This disruption in the NANCI-Nkx2.1 gene duplex results in a defective perinatal innate immune response, tissue damage, and progressive degeneration of the adult lung. These data point to a mechanism in which lncRNAs act as rheostats within lncRNA-TF gene duplex loci that buffer TF expression, thereby maintaining tissue-specific cellular identity during development and postnatal homeostasis.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Homeostasis , Pulmón/crecimiento & desarrollo , Pulmón/fisiología , Proteínas Nucleares/metabolismo , ARN Largo no Codificante/metabolismo , Factores de Transcripción/genética , Animales , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Humanos , Inmunidad Celular , Pulmón/inmunología , Ratones , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/metabolismo
11.
Nature ; 555(7695): 251-255, 2018 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-29489752

RESUMEN

Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.


Asunto(s)
Células Epiteliales/citología , Evolución Molecular , Alveolos Pulmonares/citología , Regeneración , Células Madre/citología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/cirugía , Animales , Antígenos de Superficie/metabolismo , Proteína Axina/metabolismo , Biomarcadores/metabolismo , Ciclo Celular , Linaje de la Célula , Cromatina/genética , Cromatina/metabolismo , Epigenómica , Células Epiteliales/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Masculino , Ratones , Proteínas de Neoplasias/metabolismo , Organoides/citología , Organoides/metabolismo , Células Madre/metabolismo , Transcriptoma , Vía de Señalización Wnt
12.
Genes Dev ; 30(22): 2551-2564, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27913603

RESUMEN

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1ß. Conversely, inducible expression of PGC-1ß in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1ß pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Respiración de la Célula/genética , Citoplasma/metabolismo , Eliminación de Gen , Masculino , Ratones , Mitocondrias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética
13.
Circ Res ; 127(6): 761-777, 2020 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-32529949

RESUMEN

RATIONALE: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association. OBJECTIVE: Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts. METHODS AND RESULTS: We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets. CONCLUSIONS: Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763). Graphical Abstract: A graphical abstract is available for this article.


Asunto(s)
Epigenoma , Variación Genética , Insuficiencia Cardíaca/genética , Histonas/genética , Acetilación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Inmunoprecipitación de Cromatina , Bases de Datos Genéticas , Epigénesis Genética , Epigenómica , Femenino , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Sitios de Carácter Cuantitativo
14.
BMC Ophthalmol ; 22(1): 298, 2022 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-35810276

RESUMEN

BACKGROUND: Medical services are still developing in Bhutan. There is no published national report on age-related macular degeneration (AMD). We therefore aim to determine the demographic characteristics and severity of AMD at first presentation among Bhutanese patients attending their recently inaugurated vitreoretinal (VR) clinics over a 3-year national survey, and to inform national health policy to develop suitable health program to prevent AMD-related blindness and visual impairment. METHODS: A retrospective cross-sectional consecutive case series study was conducted on all new AMD cases in Bhutan. If a patient presented with asymmetrical AMD, the eye with more severe AMD was considered. If both the eyes had the same severity one eye was chosen randomly. Collection of demographic data and clinical details including diagnostic testing (fundus photography, OCT and fluorescent angiography) and clinical staging were performed. RESULTS: Of 521 new AMD patients aged 71.9 ± 11.3 years, 306/521 (58.7%) were males (p = 0.005). At their first presentation, 234/521 patients (44.9%) already had late-stage AMD. Importantly, 69/234 patients (29.5%), that is half of total neovascular AMD (nAMD) patients, had disciform scars (DS) which were beyond treatment, and 7/234 patients (3.0%) had geographic atrophy (GA). Seven patients had retinal pigment epithelium tear at presentation. Fourteen of nineteen polypoidal choroidal vasculopathy (PCV) patients were younger than 50 years. CONCLUSIONS: Half of nAMD cases presented as DS not amenable to the treatment. Many potentially treatable nAMD patients had already lost central vision and were legally blind. Young people with PCV losing vision early in life with longer morbidity-affected life and socio-economic burden was concerning. GA and DS cases need visual rehabilitation to improve their QoL. Incorporating a screening program for AMD with effective health education, and maintaining a national AMD Registry, would potentially lower AMD-related blindness and visual impairment.


Asunto(s)
Atrofia Geográfica , Degeneración Macular Húmeda , Adolescente , Inhibidores de la Angiogénesis , Bután/epidemiología , Ceguera/epidemiología , Ceguera/etiología , Estudios Transversales , Femenino , Angiografía con Fluoresceína , Humanos , Masculino , Calidad de Vida , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular , Trastornos de la Visión , Agudeza Visual , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/epidemiología
15.
Proc Natl Acad Sci U S A ; 116(10): 4362-4371, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30782824

RESUMEN

During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal-distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.


Asunto(s)
Linaje de la Célula , Pulmón/citología , Alveolos Pulmonares/citología , Animales , Diferenciación Celular , Femenino , Hibridación Fluorescente in Situ , Ratones , Embarazo , Transcriptoma
16.
Eur Heart J ; 42(20): 2000-2011, 2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-33677556

RESUMEN

AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.


Asunto(s)
Cardiomiopatía Dilatada , Insuficiencia Cardíaca Sistólica , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Reguladoras de la Apoptosis , Cardiomiopatía Dilatada/genética , Cromosomas , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Insuficiencia Cardíaca Sistólica/genética , Humanos , Polimorfismo de Nucleótido Simple/genética
17.
Genes Dev ; 28(12): 1363-79, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24939938

RESUMEN

Long noncoding RNAs (lncRNAs) are thought to play important roles in regulating gene transcription, but few have well-defined expression patterns or known biological functions during mammalian development. Using a conservative pipeline to identify lncRNAs that have important biological functions, we identified 363 lncRNAs in the lung and foregut endoderm. Importantly, we show that these lncRNAs are spatially correlated with transcription factors across the genome. In-depth expression analyses of lncRNAs with genomic loci adjacent to the critical transcription factors Nkx2.1, Gata6, Foxa2 (forkhead box a2), and Foxf1 mimic the expression patterns of their protein-coding neighbor. Loss-of-function analysis demonstrates that two lncRNAs, LL18/NANCI (Nkx2.1-associated noncoding intergenic RNA) and LL34, play distinct roles in endoderm development by controlling expression of critical developmental transcription factors and pathways, including retinoic acid signaling. In particular, we show that LL18/NANCI acts upstream of Nkx2.1 and downstream from Wnt signaling to regulate lung endoderm gene expression. These studies reveal that lncRNAs play an important role in foregut and lung endoderm development by regulating multiple aspects of gene transcription, often through regulation of transcription factor expression.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Pulmón/crecimiento & desarrollo , ARN Largo no Codificante/metabolismo , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular/genética , Línea Celular , Endodermo/citología , Endodermo/metabolismo , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Genoma , Células HEK293 , Humanos , Pulmón/embriología , Ratones , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética , Vía de Señalización Wnt
18.
Nature ; 526(7574): 578-82, 2015 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-26436454

RESUMEN

Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.


Asunto(s)
Proteínas Hedgehog/metabolismo , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Pulmón/citología , Pulmón/metabolismo , Regeneración , Cicatrización de Heridas , Animales , Proliferación Celular , Regulación hacia Abajo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Retroalimentación Fisiológica , Proteínas Hedgehog/deficiencia , Proteínas Hedgehog/genética , Homeostasis , Pulmón/patología , Masculino , Mesodermo/citología , Mesodermo/metabolismo , Ratones , Comunicación Paracrina
19.
J Mol Cell Cardiol ; 145: 30-42, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32533974

RESUMEN

BACKGROUND: Acetylation and methylation of histones alter the chromatin structure and accessibility that affect transcriptional regulators binding to enhancers and promoters. The binding of transcriptional regulators enables the interaction between enhancers and promoters, thus affecting gene expression. However, our knowledge of these epigenetic alternations in patients with heart failure remains limited. METHODS AND RESULTS: From the comprehensive analysis of major histone modifications, 3-dimensional chromatin interactions, and transcriptome in left ventricular (LV) tissues from dilated cardiomyopathy (DCM) patients and non-heart failure (NF) donors, differential active enhancer and promoter regions were identified between NF and DCM. Moreover, the genome-wide average promoter signal is significantly lower in DCM than in NF. Super-enhancer (SE) analysis revealed that fewer SEs were found in DCM LVs than in NF ones, and three unique SE-associated genes between NF and DCM were identified. Moreover, SEs are enriched within the genomic region associated with long-range chromatin interactions. The differential enhancer-promoter interactions were observed in the known heart failure gene loci and are correlated with the gene expression levels. Motif analysis identified known cardiac factors and possible novel players for DCM. CONCLUSIONS: We have established the cistrome of four histone modifications and chromatin interactome for enhancers and promoters in NF and DCM tissues. Differential histone modifications and enhancer-promoter interactions were found in DCM, which were associated with gene expression levels of a subset of disease-associated genes in human heart failure.


Asunto(s)
Cardiomiopatía Dilatada/genética , Cromatina/metabolismo , Histonas/metabolismo , Procesamiento Proteico-Postraduccional , Factores de Transcripción/metabolismo , Secuencia de Bases , Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos , Epigénesis Genética , Ontología de Genes , Genoma Humano , Insuficiencia Cardíaca/genética , Ventrículos Cardíacos/patología , Humanos , Lisina/metabolismo , Masculino , Metilación , Proteínas Musculares/metabolismo , Motivos de Nucleótidos/genética , Regiones Promotoras Genéticas
20.
Dev Biol ; 454(2): 108-117, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31242446

RESUMEN

Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Animales , Diferenciación Celular/genética , Linaje de la Célula/fisiología , Polaridad Celular , Proliferación Celular/genética , ADN (Citosina-5-)-Metiltransferasa 1/fisiología , Metilación de ADN/genética , Endodermo/metabolismo , Epigénesis Genética/genética , Células Epiteliales/citología , Transición Epitelial-Mesenquimal , Femenino , Regulación del Desarrollo de la Expresión Génica , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Morfogénesis , Organogénesis/fisiología , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA