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1.
Mol Biol Rep ; 48(10): 6729-6738, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34436724

RESUMEN

BACKGROUND: Basal stem/progenitor cells of airway epithelium from chronic obstructive pulmonary disease (COPD) patients have a decrease in differentiation and self-renewal potential. Our study aimed at identifying deregulations in the genetic program of these cells that could account for their exhaustion, focusing on genes downstream of the epithelial-mesenchymal transition-inducing transcription factor Slug/Snail2 and responding to transforming growth factor (TGF)-ß. TGF-ß is at higher levels in COPD patient lungs, plays a role in stem/progenitor cell fate and regulates the expression of Slug/Snail2 that is highly expressed in airway basal stem/progenitors. METHODS AND RESULTS: We reanalyzed a gene expression dataset that we generated from COPD and normal primary bronchial basal progenitor cells knocked down for Slug/Snail2 gene. Among the genes that we identified to be repressed downstream of Slug/Snail2 in COPD, we selected those responding to differentiation and TGF-ß. The large majority of these genes are upregulated with differentiation but repressed by TGF-ß. Pathway and ontology enrichment analysis revealed a set of genes coding for transcription factors involved in stem cell maintenance that are repressed downstream of Slug/Snail2 and by TGF-ß in COPD but not normal basal progenitor cells. We also reveal a link between Slug/Snail2 expression and the repressive effect of TGF-ß on these stem cell maintenance genes. CONCLUSION: Our work brings a new insight and molecular perspective to the exhaustion of basal stem/progenitor cells observed in the airway epithelium of COPD patients, revealing that stem cell maintenance genes are repressed in these cells, with TGF-ß and Slug/Snail2 being involved in this deregulation.


Asunto(s)
Bronquios/patología , Epitelio/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Factores de Transcripción de la Familia Snail/metabolismo , Células Madre/metabolismo , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/metabolismo
2.
Psychiatry Res ; 309: 114398, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35066309

RESUMEN

During the first wave of COVID-19, nearly 50% of France's fatalities occurred in nursing homes. Older people with mental health disorders are considered to be more prone to infections when epidemics arise. To test this hypothesis, we conducted a retrospective descriptive and comparative study of the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a cohort of elderly residents with or without severe mental illness (SMI) living in a French nursing home facility. This was done during the first lockdown from March 17th until May 11th, 2020. Our study included 72 participants of 75 residents, of whom 58 contracted COVID-19, 14 developed a severe form requiring hospitalisation, and 14 died. The disease was significantly less frequent in residents with SMI 15(62%) than those without SMI 43 (89.6%). In regression analysis, a higher level of autonomy was significantly associated with a lower disease incidence. Once contracted, residents with or without SMI differed significantly neither on morbidity nor mortality. The period of survival did not either significantly differ between the two groups. As a potential explanation, we suggested that pathological social withdrawal added to stigmatisation could have protected SMI residents from contracting the disease.


Asunto(s)
COVID-19 , Trastornos Mentales , Anciano , Control de Enfermedades Transmisibles , Humanos , Incidencia , Trastornos Mentales/epidemiología , Casas de Salud , Pandemias , Estudios Retrospectivos , SARS-CoV-2
3.
Stem Cell Rev Rep ; 17(3): 703-718, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33495975

RESUMEN

Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-ß in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-ß, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-ß are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-ß,we show that there is positive correlations between the effect of differentiation and TGF-ß on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and ß-Catenin, two molecules from TGF-ßsignaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-ß-induced mechanisms.


Asunto(s)
Bronquios , Enfermedad Pulmonar Obstructiva Crónica , Factores de Transcripción de la Familia Snail , Células Madre , Factor de Crecimiento Transformador beta , Adulto , Bronquios/citología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Proliferación Celular , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología
4.
Mol Biol Cell ; 18(5): 1943-52, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17344479

RESUMEN

Transcription factors of the Snail family are key regulators of epithelial-mesenchymal transition (EMT). In many processes during development or disease, cells do not acquire all the characteristics associated with EMT, leading to what we refer to as partial EMT (p-EMT). However, little is known of the implications of the Snail transcription factors in processes that only involve a p-EMT. To assess this, we used the hepatocyte growth factor (HGF)-induced Madin-Darby canine kidney tubulogenesis system, which provides a three-dimensional culture model of a morphogenetic process including a p-EMT. We found that although Slug (Snail2) is highly and transitory up-regulated during the p-EMT phase of tubulogenesis, it is not a repressor of E-cadherin during this process. Using inducible knockdown of Slug, we demonstrate that Slug is not an inducer of cell movement and instead is required for survival during p-EMT. We conclude that in epithelial cells, promoting cell survival can be a primary function of Slug, rather than being acquired concomitantly with EMT.


Asunto(s)
Supervivencia Celular/fisiología , Factor de Crecimiento de Hepatocito/farmacología , Túbulos Renales/crecimiento & desarrollo , Túbulos Renales/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Cadherinas/genética , Línea Celular , Núcleo Celular/metabolismo , Cartilla de ADN/genética , Perros , Epitelio/efectos de los fármacos , Epitelio/crecimiento & desarrollo , Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Mesodermo/citología , Mesodermo/efectos de los fármacos , Mesodermo/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción de la Familia Snail , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Transfección , Regulación hacia Arriba/efectos de los fármacos
5.
Mol Biol Cell ; 16(2): 433-45, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15574881

RESUMEN

Epithelial cells polarize and orient polarity in response to cell-cell and cell-matrix adhesion. Although there has been much recent progress in understanding the general polarizing machinery of epithelia, it is largely unclear how this machinery is controlled by the extracellular environment. To explore the signals from cell-matrix interactions that control orientation of cell polarity, we have used three-dimensional culture systems in which Madin-Darby canine kidney (MDCK) cells form polarized, lumen-containing structures. We show that interaction of collagen I with apical beta1-integrins after collagen overlay of a polarized MDCK monolayer induces activation of Rac1, which is required for collagen overlay-induced tubulocyst formation. Cysts, comprised of a monolayer enclosing a central lumen, form after embedding single cells in collagen. In those cultures, addition of a beta1-integrin function-blocking antibody to the collagen matrix gives rise to cysts that have defects in the organization of laminin into the basement membrane and have inverted polarity. Normal polarity is restored by either expression of activated Rac1, or the inclusion of excess laminin-1 (LN-1). Together, our results suggest a signaling pathway in which the activation of beta1-integrins orients the apical pole of polarized cysts via a mechanism that requires Rac1 activation and laminin organization into the basement membrane.


Asunto(s)
Polaridad Celular , Células Epiteliales/fisiología , Integrinas/metabolismo , Laminina/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Animales , Adhesión Celular , Técnicas de Cultivo de Célula , Línea Celular , Colágeno Tipo I/metabolismo , Perros , Activación Enzimática , Células Epiteliales/ultraestructura
6.
J Agric Food Chem ; 55(14): 5834-41, 2007 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-17567033

RESUMEN

Two-dimensional electrophoresis was used to compare Longissimus sarcoplasmic protein abundance between two groups (tough meat and tender meat), defined on the basis of extreme Warner-Bratzler shear force values measured on cooked pork. Fourteen protein spots differed in quantity (P<0.05) between the two groups and were identified. Adypocyte fatty acid binding protein and acyl-CoA binding protein involved in lipid traffic and in the control of gene expression regulating cell proliferation and differentiation, and Enoyl-CoA hydratase, aldose reductase and triosephosphate isomerase indirectly related to lipid metabolism were overrepresented in the tender group. The tender group was further characterized by increased levels of proteins involved in protein folding and polymerization (initiation factor elf-3beta, chaperonin subunit 2, profilin II). The results suggest that the lower post-cooking shear force could at least in part be related to muscle adipogenetic and/or myogenetic status of which the possible underlying mechanisms are discussed.


Asunto(s)
Calor , Carne , Músculo Esquelético/química , Proteoma/análisis , Retículo Sarcoplasmático/química , Porcinos , Animales , Tecnología de Alimentos , Proteínas Musculares/análisis , Resistencia al Corte
7.
Novartis Found Symp ; 269: 193-200; discussion 200-5, 223-30, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16355541

RESUMEN

The kidney is primarily comprised of highly polarized epithelial cells. Much has been learned recently about the mechanisms of epithelial polarization. However, in most experimental systems the orientation of this polarity is determined by external cues, such as growth of epithelial cells on a filter support. When Madin-Darby canine kidney (MDCK) cells are grown instead in a three-dimensional (3D) collagen gel, the cells form hollow cysts lined by a monolayer of epithelial cells, with their apical surfaces all facing the central lumen. We have found that expression of a dominant-negative (DN) form of the small GTPase Rac1 causes an inversion of epithelial polarity, such that the apical surface of the cells instead faces the periphery of the cyst. This indicates that the establishment of polarity and the orientation of polarity can be experimentally separated by growing cells in a 3D collagen gel, where there is no filter support to provide an external cue for orientation. DN Rac1 causes a defect in the assembly of laminin into its normal basement membrane network, and addition of a high concentration of exogenous laminin rescues the inversion of polarity caused by DN Rac1.


Asunto(s)
Células Epiteliales/citología , Células Epiteliales/metabolismo , Animales , Comunicación Celular , Línea Celular , Polaridad Celular , Colágeno , Perros , Células Epiteliales/efectos de los fármacos , Factor de Crecimiento de Hepatocito/farmacología , Uniones Estrechas/fisiología , Proteína de Unión al GTP rac1/metabolismo
8.
J Leukoc Biol ; 75(4): 680-8, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-14704364

RESUMEN

Hox genes, which are key regulators of cell fate and pattern formation during embryogenesis, are also important regulators of hematopoiesis, and different combinations of Hox gene products are involved in lineage commitment or maturation. However, their molecular and cellular modes of action are not yet completely understood. Recent studies have indicated that Hox genes are involved in the regulation of cell-extracellular matrix (ECM) interactions and cell migration. Here, we report that Hox A7, a gene frequently overexpressed in acute myeloid leukemia, is down-regulated during HL-60 monocytic differentiation. Using a model in which HL-60 cells are induced to differentiate toward the monocytic lineage with bone marrow stromal-like cells, we demonstrate that Hox A7-sustained expression disturbs the regulation of cell adhesive and migratory capacities on fibronectin during early differentiation. We show that this is accompanied by a partial blockage of the transcriptional induction of proline-rich tyrosine kinase 2, a gene coding for a focal adhesion kinase active in monocytes, and of tissue transglutaminase, a gene coding for a fibronectin coreceptor in monocytes. This is the first report that demonstrates the involvement of a Hox gene in the regulation of adhesion and migration of hematopoietic cells and that links it to the deregulation of genes involved in cell-ECM interactions and downstream signaling pathways.


Asunto(s)
Diferenciación Celular/genética , Movimiento Celular/genética , Regulación hacia Abajo/genética , Fibronectinas/metabolismo , Proteínas de Homeodominio/metabolismo , Monocitos/metabolismo , Proteínas de Neoplasias/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Técnicas de Cocultivo , Fibronectinas/farmacología , Quinasa 2 de Adhesión Focal , Regulación del Desarrollo de la Expresión Génica/genética , Células HL-60 , Proteínas de Homeodominio/genética , Humanos , Integrina alfa5beta1/genética , Integrina alfa5beta1/metabolismo , Integrinas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Monocitos/citología , Monocitos/efectos de los fármacos , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células del Estroma/metabolismo , Transcripción Genética/genética , Transglutaminasas/genética , Transglutaminasas/metabolismo
9.
PLoS One ; 10(6): e0127283, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26035830

RESUMEN

BACKGROUND: Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. METHODS: To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay]. RESULTS: Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9ß1 integrin-dependent manner. CONCLUSIONS: Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.


Asunto(s)
Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Inflamación/inducido químicamente , Osteopontina/genética , Ozono/efectos adversos , Adulto , Aire Acondicionado , Broncoscopía , Línea Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Osteopontina/metabolismo , Osteopontina/farmacología , Estrés Oxidativo/efectos de los fármacos , Ozono/administración & dosificación
10.
J Invest Dermatol ; 129(2): 491-5, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18685621

RESUMEN

Many peptide growth factors, including EGFR ligands, accelerate wound reepithelialization in vivo and in vitro. Furthermore, EGFR expression is transiently increased at wound margins, suggesting an active role for this receptor in wound repair. During reepithelialization of cutaneous wounds, keratinocytes display a phenotypic plasticity resembling aspects of epithelial-mesenchymal transformation. The transcription factor Slug/Snai2 is a regulator of epithelial-mesenchymal transformation during development, and we previously reported that Slug expression is elevated in keratinocytes bordering cutaneous wounds in vivo, ex vivo, and in vitro. In this study we provide evidence that Slug expression is necessary for an EGFR-stimulated reepithelialization response. Epidermal growth factor (EGF) induces Slug expression and the response to EGFR activation is more robust than to other receptor tyrosine kinase ligands. EGFR-stimulated reepithelialization is highly dependent on Slug, as demonstrated by the absence of EGF-stimulated outgrowth in explants derived from Slug null mice. In vitro reepithelialization stimulated by ectopic Slug expression was not impaired by an inhibitor of EGFR catalytic activity, suggesting that Slug is a downstream mediator of this EGFR-stimulated response. Our findings provide evidence that Slug is an essential component of the pathway leading to EGFR-mediated epithelial outgrowth.


Asunto(s)
Receptores ErbB/metabolismo , Queratinocitos/citología , Queratinocitos/fisiología , Factores de Transcripción/metabolismo , Cicatrización de Heridas/fisiología , Animales , Línea Celular , Expresión Génica/fisiología , Humanos , Operón Lac , Ratones , Ratones Transgénicos , Regeneración/fisiología , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética
11.
Eur J Haematol ; 70(1): 43-52, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12631258

RESUMEN

Permanent osteoblastic cell lines are potential tools to study the interactions between osteoblastic and hematopoietic cells in the bone marrow cavity. In a recent work we have shown that the osteosarcoma cell line CAL72 may be more closely related to normal osteoblasts than the osteosarcoma cells previously described. In the present work we continued the characterisation of the CAL72 cell line with regard to its effects on various hematopoietic cells, in coculture experiments. We show here that CAL72 cells, in contrast to MG-63 or SaOS-2 osteosarcoma cell lines, do not inhibit hematopoietic colony formation and sustain the limited expansion of hematopoietic progenitors in a similar way to that described for normal osteoblasts. We also demonstrate that CAL72 cells induce the monocytic differentiation of the promyelocytic HL-60 cell line like MG-63 and SaOS-2, but support a better maturation and a longer survival of the differentiated cells than the two other osteosarcoma cell lines. In order to better understand the differential effects observed between CAL72 and MG-63 or SaOS-2, we analysed the cytokine and chemokine mRNA expression of these cells using the RNase protection quantitative assay. We show here that the expression profile of CAL72 is clearly different from that of MG-63 or SaOS-2 and may explain, at least in part, its specific effects on hematopoietic cells. Taken together these experiments confirm that CAL72 has particular properties and is an interesting tool to study the role of osteoblastic cells in hematopoietic cell growth and differentiation.


Asunto(s)
Comunicación Celular , Células Madre Hematopoyéticas/citología , Osteoblastos/fisiología , Células Tumorales Cultivadas/citología , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Neoplasias de la Médula Ósea/patología , Diferenciación Celular , División Celular , Técnicas de Cocultivo , Sangre Fetal/citología , Células HL-60 , Hematopoyesis , Humanos , Osteosarcoma/patología
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