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1.
Int J Mol Sci ; 25(7)2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38612630

RESUMEN

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases, including oral cancer. Cancer cells usually escape from the immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα, in the tumor microenvironment of oral squamous cell carcinoma (OSCC), performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating to seven immune-related factors and several clinicopathological statuses. However, the immune checkpoint-related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that the keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference in tumor immunity in the originating epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC, might be different in the originating epithelium, keratinized or non-keratinized.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Antígeno B7-H1 , Antígeno CD47 , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , Epitelio , Microambiente Tumoral
2.
Int J Mol Sci ; 25(7)2024 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-38612698

RESUMEN

Helicobacter pylori (H. pylori) infection induces DNA Double-Strand Breaks (DSBs) and consequently activates the DNA Damage Response pathway (DDR) and senescence in gastric epithelium. We studied DDR activation and senescence before and after the eradication of the pathogen. Gastric antral and corpus biopsies of 61 patients with H. pylori infection, prior to and after eradication treatment, were analyzed by means of immunohistochemistry/immunofluorescence for DDR marker (γH2AΧ, phosporylated ataxia telangiectasia-mutated (pATM), p53-binding protein (53BP1) and p53) expression. Samples were also evaluated for Ki67 (proliferation index), cleaved caspase-3 (apoptotic index) and GL13 staining (cellular senescence). Ten H. pylori (-) dyspeptic patients served as controls. All patients were re-endoscoped in 72-1361 days (mean value 434 days), and tissue samples were processed in the same manner. The eradication of the microorganism, in human gastric mucosa, downregulates γH2AΧ expression in both the antrum and corpus (p = 0.00019 and p = 0.00081 respectively). The expression of pATM, p53 and 53BP1 is also reduced after eradication. Proliferation and apoptotic indices were reduced, albeit not significantly, after pathogen clearance. Moreover, cellular senescence is increased in H. pylori-infected mucosa and remains unaffected after eradication. Interestingly, senescence was statistically increased in areas of intestinal metaplasia (IM) compared with adjacent non-metaplastic mucosa (p < 0.001). In conclusion, H. pylori infection triggers DSBs, DDR and senescence in the gastric epithelium. Pathogen eradication reverses the DDR activation but not senescence. Increased senescent cells may favor IM persistence, thus potentially contributing to gastric carcinogenesis.


Asunto(s)
Helicobacter pylori , Humanos , Proteína p53 Supresora de Tumor/genética , Mucosa Gástrica , Reparación del ADN , Epitelio
3.
Rev Esp Patol ; 57(2): 133-136, 2024.
Artículo en Español | MEDLINE | ID: mdl-38599734

RESUMEN

Esophagitis dissecans superficialis (EDS) is a rare disease characterized by sloughing of the superficial esophageal mucosa and, histologically, by the bitonal appearance of the squamous epithelium secondary to necrosis of the most superficial layers. Etiology is uncertain, however, it has been associated with some medications, autoimmune diseases, esophageal stasis and endoscopic procedures. Here, two cases are presented, one of them which appeared in a woman after an episode of dysphagia and another one which occurred to a man with comorbidities and epigastric pain. This entity should be considered due to its self-limiting clinical course, compared to other entities with a more torpid evolution or that require more specific treatment.


Asunto(s)
Enfermedades Autoinmunes , Esofagitis , Masculino , Femenino , Humanos , Esofagitis/complicaciones , Esofagitis/patología , Epitelio/patología
4.
Int J Mol Sci ; 25(7)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38612536

RESUMEN

The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We hypothesized that the interplay between hormone-induced changes in the mechanical properties of the endometrial epithelium and stroma supports this process. To study it, we used hormone-responsive endometrial adenocarcinoma-derived Ishikawa cells growing on substrates of different stiffness. We showed that Ishikawa monolayers on soft substrates are more tightly clustered and uniform than on stiff substrates. Probing for mechanical alterations, we found accelerated stress-relaxation after apical nanoindentation in hormone-stimulated monolayers on stiff substrates. Traction force microscopy furthermore revealed an increased number of foci with high traction in the presence of estradiol and progesterone on soft substrates. The detection of single cells and small cell clusters positive for the intermediate filament protein vimentin and the progesterone receptor further underscored monolayer heterogeneity. Finally, adhesion assays with trophoblast-derived AC-1M-88 spheroids were used to examine the effects of substrate stiffness and steroid hormones on endometrial receptivity. We conclude that the extracellular matrix and hormones act together to determine mechanical properties and, ultimately, embryo implantation.


Asunto(s)
Matriz Extracelular , Progesterona , Femenino , Humanos , Epitelio , Ciclo Menstrual , Estradiol
5.
Nat Commun ; 15(1): 3000, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38589403

RESUMEN

Actomyosin networks constrict cell area and junctions to alter cell and tissue shape. However, during cell expansion under mechanical stress, actomyosin networks are strengthened and polarized to relax stress. Thus, cells face a conflicting situation between the enhanced actomyosin contractile properties and the expansion behaviour of the cell or tissue. To address this paradoxical situation, we study late Drosophila oogenesis and reveal an unusual epithelial expansion wave behaviour. Mechanistically, Rac1 and Rho1 integrate basal pulsatile actomyosin networks with ruffles and focal adhesions to increase and then stabilize basal area of epithelial cells allowing their flattening and elongation. This epithelial expansion behaviour bridges cell changes to oocyte growth and extension, while oocyte growth in turn deforms the epithelium to drive cell spreading. Basal pulsatile actomyosin networks exhibit non-contractile mechanics, non-linear structures and F-actin/Myosin-II spatiotemporal signal separation, implicating unreported expanding properties. Biophysical modelling incorporating these expanding properties well simulates epithelial cell expansion waves. Our work thus highlights actomyosin expanding properties as a key mechanism driving tissue morphogenesis.


Asunto(s)
Actomiosina , Proteínas de Drosophila , Animales , Actomiosina/metabolismo , Proteínas de Drosophila/metabolismo , Células Epiteliales/metabolismo , Citoesqueleto de Actina/metabolismo , Drosophila/metabolismo , Epitelio/metabolismo , Morfogénesis
6.
PLoS Comput Biol ; 20(4): e1012001, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38557605

RESUMEN

Epithelial tissues are the most abundant tissue type in animals, lining body cavities and generating compartment barriers. The function of a monolayered epithelial tissue-whether protective, secretory, absorptive, or filtrative-relies on the side-by-side arrangement of its component cells. The mechanical parameters that determine the shape of epithelial cells in the apical-basal plane are not well-understood. Epithelial tissue architecture in culture is intimately connected to cell density, and cultured layers transition between architectures as they proliferate. This prompted us to ask to what extent epithelial architecture emerges from two mechanical considerations: A) the constraints of densification and B) cell-cell adhesion, a hallmark feature of epithelial cells. To address these questions, we developed a novel polyline cell-based computational model and used it to make theoretical predictions about epithelial architecture upon changes to density and cell-cell adhesion. We tested these predictions using cultured cell experiments. Our results show that the appearance of extended lateral cell-cell borders in culture arises as a consequence of crowding-independent of cell-cell adhesion. However, cadherin-mediated cell-cell adhesion is associated with a novel architectural transition. Our results suggest that this transition represents the initial appearance of a distinctive epithelial architecture. Together our work reveals the distinct mechanical roles of densification and adhesion to epithelial layer formation and provides a novel theoretical framework to understand the less well-studied apical-basal plane of epithelial tissues.


Asunto(s)
Cadherinas , Células Epiteliales , Animales , Epitelio , Adhesión Celular , Células Cultivadas
7.
Sci Adv ; 10(14): eadj7666, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38569041

RESUMEN

Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Prostaglandinas , Humanos , Epitelio/metabolismo , Inflamación , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Fibroblastos/metabolismo
8.
Virol J ; 21(1): 78, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38566231

RESUMEN

Chronic obstructive pulmonary disease (COPD) affects over 250 million individuals globally and stands as the third leading cause of mortality. Respiratory viral infections serve as the primary drivers of acute exacerbations, hastening the decline in lung function and worsening the prognosis. Notably, Human Parainfluenza Virus type 3 (HPIV-3) is responsible for COPD exacerbations with a frequency comparable to that of Respiratory Syncytial Virus and Influenza viruses. However, the impact of HPIV-3 on respiratory epithelium within the context of COPD remains uncharacterized.In this study, we employed in vitro reconstitution of lower airway epithelia from lung tissues sourced from healthy donors (n = 4) and COPD patients (n = 5), maintained under air-liquid interface conditions. Through a next-generation sequencing-based transcriptome analysis, we compared the cellular response to HPIV-3 infection.Prior to infection, COPD respiratory epithelia exhibited a pro-inflammatory profile, notably enriched in canonical pathways linked to antiviral response, B cell signaling, IL-17 signaling, and epithelial-mesenchymal transition, in contrast to non-COPD epithelia. Intriguingly, post HPIV-3 infection, only non-COPD epithelia exhibited significant enrichment in interferon signaling, pattern recognition receptors of viruses and bacteria, and other pathways involved in antiviral responses. This deficiency could potentially hinder immune cell recruitment essential for controlling viral infections, thus fostering prolonged viral presence and persistent inflammation.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Virus Sincitial Respiratorio Humano , Virosis , Virus , Humanos , Virus de la Parainfluenza 3 Humana , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Epitelio , Antivirales/uso terapéutico
9.
Sci Prog ; 107(2): 368504241232537, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38567422

RESUMEN

Nasopharyngeal carcinoma is a malignant tumor that occurs in the epithelium and mucosal glands of the nasopharynx, and its pathological type is mostly poorly differentiated squamous cell carcinoma. Since the nasopharynx is located deep in the head and neck, early diagnosis and timely treatment are critical to patient survival. However, nasopharyngeal carcinoma tumors are small in size and vary widely in shape, and it is also a challenge for experienced doctors to delineate tumor contours. In addition, due to the special location of nasopharyngeal carcinoma, complex treatments such as radiotherapy or surgical resection are often required, so accurate pathological diagnosis is also very important for the selection of treatment options. However, the current deep learning segmentation model faces the problems of inaccurate segmentation and unstable segmentation process, which are mainly limited by the accuracy of data sets, fuzzy boundaries, and complex lines. In order to solve these two challenges, this article proposes a hybrid model WET-UNet based on the UNet network as a powerful alternative for nasopharyngeal cancer image segmentation. On the one hand, wavelet transform is integrated into UNet to enhance the lesion boundary information by using low-frequency components to adjust the encoder at low frequencies and optimize the subsequent computational process of the Transformer to improve the accuracy and robustness of image segmentation. On the other hand, the attention mechanism retains the most valuable pixels in the image for us, captures the remote dependencies, and enables the network to learn more representative features to improve the recognition ability of the model. Comparative experiments show that our network structure outperforms other models for nasopharyngeal cancer image segmentation, and we demonstrate the effectiveness of adding two modules to help tumor segmentation. The total data set of this article is 5000, and the ratio of training and verification is 8:2. In the experiment, accuracy = 85.2% and precision = 84.9% can show that our proposed model has good performance in nasopharyngeal cancer image segmentation.


Asunto(s)
Neoplasias Nasofaríngeas , Humanos , Neoplasias Nasofaríngeas/diagnóstico por imagen , Carcinoma Nasofaríngeo/diagnóstico por imagen , Epitelio , Cuello
10.
Cell Mol Life Sci ; 81(1): 159, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38558087

RESUMEN

Both EphB2- and EphB3-deficient mice exhibit profound histological alterations in the thymic epithelial network but few changes in T-cell differentiation, suggesting that this organization would be sufficient to produce functional T lymphocytes. Also, other antigen-presenting cells involved in immunological education could substitute the thymic epithelium. Accordingly, we found an increased frequency of plasmacytoid dendritic cells but not of conventional dendritic cells, medullary fibroblasts or intrathymic B lymphocytes. In addition, there are no lymphoid infiltrates in the organs of mutant mice nor do they contain circulating autoantibodies. Furthermore, attempts to induce arthritic lesions after chicken type II collagen administration fail totally in EphB2-deficient mice whereas all WT and half of the immunized EphB3-/- mice develop a typical collagen-induced arthritis. Our results point out that Th17 cells, IL4-producing Th2 cells and regulatory T cells are key for the induction of disease, but mutant mice appear to have deficits in T cell activation or cell migration properties. EphB2-/- T cells show reduced in vitro proliferative responses to anti-CD3/anti-CD28 antibodies, produce low levels of anti-type II collagen antibodies, and exhibit low proportions of T follicular helper cells. On the contrary, EphB3-/- lymph node cells respond accurately to the different immune stimuli although in lower levels than WT cells but show a significantly reduced migration in in vitro transwell assays, suggesting that no sufficient type II collagen-dependent activated lymphoid cells reached the joints, resulting in reduced arthritic lesions.


Asunto(s)
Artritis Experimental , Animales , Ratones , Colágeno , Colágeno Tipo II , Epitelio , Timo , Receptor EphB3/metabolismo
11.
Curr Protoc ; 4(4): e1027, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38588063

RESUMEN

The development of patient-derived intestinal organoids represents an invaluable model for simulating the native human intestinal epithelium. These stem cell-rich cultures outperform commonly used cell lines like Caco-2 and HT29-MTX in reflecting the cellular diversity of the native intestinal epithelium after differentiation. In our recent study examining the effects of polystyrene (PS), microplastics (MPs), and nanoplastics (NPs), widespread pollutants in our environment and food chain, on the human intestinal epithelium, these organoids have been instrumental in elucidating the absorption mechanisms and potential biological impacts of plastic particles. Building on previously established protocols in human intestinal organoid culture, we herein detail a streamlined protocol for the cultivation, differentiation, and generation of organoid-derived monolayers. This protocol is tailored to generate monolayers incorporating microfold cells (M cells), key for intestinal particle uptake but often absent in current in vitro models. We provide validated protocols for the characterization of MPs/NPs via scanning electron microscopy (SEM) for detailed imaging and their introduction to intestinal epithelial monolayer cells via confocal immunostaining. Additionally, protocols to test the impacts of MP/NP exposure on the functions of the intestinal barrier using transendothelial electrical resistance (TEER) measurements and assessing inflammatory responses using cytokine profiling are detailed. Overall, our protocols enable the generation of human intestinal organoid monolayers, complete with the option of including or excluding M cells, offering crucial techniques for observing particle uptake and identifying inflammatory responses in intestinal epithelial cells to advance our knowledge of the potential effects of plastic pollution on human gut health. These approaches are also amendable to the study of other gut-related chemical and biological exposures and physiological responses due to the robust nature of the systems. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Human intestinal organoid culture and generation of monolayers with and without M cells Support Protocol 1: Culture of L-WRN and production of WRN-conditioned medium Support Protocol 2: Neuronal cell culture and integration into intestinal epithelium Support Protocol 3: Immune cell culture and integration into intestinal epithelium Basic Protocol 2: Scanning electron microscopy: sample preparation and imaging Basic Protocol 3: Immunostaining and confocal imaging of MP/NP uptake in organoid-derived monolayers Basic Protocol 4: Assessment of intestinal barrier function via TEER measurements Basic Protocol 5: Cytokine profiling using ELISA post-MP/NP exposure.


Asunto(s)
Microplásticos , Plásticos , Humanos , Microplásticos/metabolismo , Células CACO-2 , Plásticos/metabolismo , Mucosa Intestinal/metabolismo , Organoides , Epitelio , Citocinas/metabolismo
12.
Int J Dev Biol ; 68(1): 39-45, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38591692

RESUMEN

Keratin 17 (K17) is thought to be a candidate target gene for regulation by Lymphoid Enhancer Factor-1 (Lef-1). K17 is a marker that distinguishes junctional epithelium (JE) from epithelial rests of Malassez (ERM). However, the relationship of Lef-1 to K17 is not clear in this context. Moreover, the expression of other keratins such as K5, K6, K7 and K16 is not reported. Therefore, the aim of our study was to assay the expression of K5, K6, K7, K14, K16, K17 and Lef-1 in postnatal developing teeth, and clarify the corresponding immunophenotypes of the JE and ERM. Upper jaws of Wistar rats aged from postnatal (PN) day 3.5 to PN21 were used and processed for immunohistochemistry. K5 and K14 were intensely expressed in inner enamel epithelium (IEE), reduced enamel epithelium (REE), ERM and JE. There was no staining for K16 in the tissue, except for strong staining in the oral epithelium. Specifically, at PN3.5 and PN7, K17 was initially strongly expressed and then negative in the IEE. At PN16 and PN21, both REE and ERM were strongly stained for K17, whereas K17 was negative in the JE. In addition, K6, K7 and Lef-1 were not detected in any tissue investigated. REE and ERM have an identical keratin expression pattern before eruption, while JE differs from ERM in the expression of K17 after eruption. The expression of K17 does not coincide with that of Lef-1. These data indicate that JE has a unique phenotype different from ERM, which is of odontogenic origin.


Asunto(s)
Inserción Epitelial , Descanso , Ratas , Animales , Inserción Epitelial/metabolismo , Ratas Wistar , Epitelio/metabolismo , Inmunohistoquímica , Queratinas/metabolismo
13.
PeerJ ; 12: e16964, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38560455

RESUMEN

Within-host infection dynamics of Omicron dramatically differs from previous variants of SARS-CoV-2. However, little is still known about which parameters of virus-cell interplay contribute to the observed attenuated replication and pathogenicity of Omicron. Mathematical models, often expressed as systems of differential equations, are frequently employed to study the infection dynamics of various viruses. Adopting such models for results of in vitro experiments can be beneficial in a number of aspects, such as model simplification (e.g., the absence of adaptive immune response and innate immunity cells), better measurement accuracy, and the possibility to measure additional data types in comparison with in vivo case. In this study, we consider a refinement of our previously developed and validated model based on a system of integro-differential equations. We fit the model to the experimental data of Omicron and Delta infections in Caco-2 (human intestinal epithelium model) and Calu-3 (lung epithelium model) cell lines. The data include known information on initial conditions, infectious virus titers, and intracellular viral RNA measurements at several time points post-infection. The model accurately explains the experimental data for both variants in both cell lines using only three variant- and cell-line-specific parameters. Namely, the cell entry rate is significantly lower for Omicron, and Omicron triggers a stronger cytokine production rate (i.e., innate immune response) in infected cells, ultimately making uninfected cells resistant to the virus. Notably, differences in only a single parameter (e.g., cell entry rate) are insufficient to obtain a reliable model fit for the experimental data.


Asunto(s)
COVID-19 , Humanos , Células CACO-2 , SARS-CoV-2 , Epitelio , Modelos Teóricos
14.
Development ; 151(8)2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38512712

RESUMEN

The formation of complex three-dimensional organs during development requires precise coordination between patterning networks and mechanical forces. In particular, tissue folding is a crucial process that relies on a combination of local and tissue-wide mechanical forces. Here, we investigate the contribution of cell proliferation to epithelial morphogenesis using the Drosophila leg tarsal folds as a model. We reveal that tissue-wide compression forces generated by cell proliferation, in coordination with the Notch signaling pathway, are essential for the formation of epithelial folds in precise locations along the proximo-distal axis of the leg. As cell numbers increase, compressive stresses arise, promoting the folding of the epithelium and reinforcing the apical constriction of invaginating cells. Additionally, the Notch target dysfusion plays a key function specifying the location of the folds, through the apical accumulation of F-actin and the apico-basal shortening of invaginating cells. These findings provide new insights into the intricate mechanisms involved in epithelial morphogenesis, highlighting the crucial role of tissue-wide forces in shaping a three-dimensional organ in a reproducible manner.


Asunto(s)
Proteínas de Drosophila , Drosophila , Animales , Drosophila/metabolismo , Epitelio/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Morfogénesis/genética , Proliferación Celular , Transducción de Señal , Drosophila melanogaster/metabolismo
15.
Elife ; 122024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38466627

RESUMEN

Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.


Asunto(s)
Timocitos , Factores de Transcripción , Ratones , Animales , Timocitos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones Endogámicos C57BL , Timo/metabolismo , Diferenciación Celular , Células Epiteliales/metabolismo , Epitelio/metabolismo
16.
Results Probl Cell Differ ; 72: 119-126, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38509255

RESUMEN

Many organs are composed of epithelial and mesenchymal tissue components. These two tissue component types develop via reciprocal interactions. However, for historical and technical reasons, the effects of the mesenchymal components on the epithelium have been emphasized. Well-documented examples are the regionally specific differentiation of the endoderm-derived primitive gut tube under the influence of surrounding mesenchyme. In contrast to a pile of reports on mesenchyme-derived signaling mechanisms, few studies have depicted the epithelial action in depth. This chapter highlights an example of an opposite action from the epithelial side, which was found in esophagus development.


Asunto(s)
Organogénesis , Transducción de Señal , Epitelio , Mesodermo , Diferenciación Celular
17.
Sci Rep ; 14(1): 6774, 2024 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-38514727

RESUMEN

Biophysical cues from the cell microenvironment are detected by mechanosensitive components at the cell surface. Such machineries convert physical information into biochemical signaling cascades within cells, subsequently leading to various cellular responses in a stimulus-dependent manner. At the surface of extracellular environment and cell cytoplasm exist several ion channel families that are activated by mechanical signals to direct intracellular events. One of such channel is formed by transient receptor potential cation channel subfamily V member, TRPV4 that is known to act as a mechanosensor in wide variaty of tissues and control ion-influx in a spatio-temporal way. Here we report that TRPV4 is prominently expressed in the stem/progenitor cell populations of the mammary epithelium and seems important for the lineage-specific differentiation, consequently affecting mechanical features of the mature mammary epithelium. This was evident by the lack of several markers for mature myoepithelial and luminal epithelial cells in TRPV4-depleted cell lines. Interestingly, TRPV4 expression is controlled in a tension-dependent manner and it also impacts differentation process dependently on the stiffness of the microenvironment. Furthermore, such cells in a 3D compartment were disabled to maintain normal mammosphere structures and displayed abnormal lumen formation, size of the structures and disrupted cellular junctions. Mechanosensitive TRPV4 channel therefore act as critical player in the homeostasis of normal mammary epithelium through sensing the physical environment and guiding accordingly differentiation and structural organization of the bilayered mammary epithelium.


Asunto(s)
Transducción de Señal , Canales Catiónicos TRPV , Humanos , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Epitelio/metabolismo , Células Epiteliales/metabolismo , Citoplasma/metabolismo
18.
Sci Rep ; 14(1): 6750, 2024 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-38514730

RESUMEN

Signals for the maintenance of epithelial homeostasis are provided in part by commensal bacteria metabolites, that promote tissue homeostasis in the gut and remote organs as microbiota metabolites enter the bloodstream. In our study, we investigated the effects of bile acid metabolites, 3-oxolithocholic acid (3-oxoLCA), alloisolithocholic acid (AILCA) and isolithocholic acid (ILCA) produced from lithocholic acid (LCA) by microbiota, on the regulation of innate immune responses connected to the expression of host defense peptide cathelicidin in lung epithelial cells. The bile acid metabolites enhanced expression of cathelicidin at low concentrations in human bronchial epithelial cell line BCi-NS1.1 and primary bronchial/tracheal cells (HBEpC), indicating physiological relevance for modulation of innate immunity in airway epithelium by bile acid metabolites. Our study concentrated on deciphering signaling pathways regulating expression of human cathelicidin, revealing that LCA and 3-oxoLCA activate the surface G protein-coupled bile acid receptor 1 (TGR5, Takeda-G-protein-receptor-5)-extracellular signal-regulated kinase (ERK1/2) cascade, rather than the nuclear receptors, aryl hydrocarbon receptor, farnesoid X receptor and vitamin D3 receptor in bronchial epithelium. Overall, our study provides new insights into the modulation of innate immune responses by microbiota bile acid metabolites in the gut-lung axis, highlighting the differences in epithelial responses between different tissues.


Asunto(s)
Ácidos y Sales Biliares , Catelicidinas , Humanos , Ácidos y Sales Biliares/metabolismo , Catelicidinas/metabolismo , Sistema de Señalización de MAP Quinasas , Receptores Acoplados a Proteínas G/metabolismo , Epitelio/metabolismo , Ácido Litocólico/farmacología , Ácido Litocólico/metabolismo
19.
PeerJ ; 12: e16974, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38435996

RESUMEN

We investigate the behavior of systems of cells with intracellular molecular oscillators ("clocks") where cell-cell adhesion is mediated by differences in clock phase between neighbors. This is motivated by phenomena in developmental biology and in aggregative multicellularity of unicellular organisms. In such systems, aggregation co-occurs with clock synchronization. To account for the effects of spatially extended cells, we use the Cellular Potts Model (CPM), a lattice agent-based model. We find four distinct possible phases: global synchronization, local synchronization, incoherence, and anti-synchronization (checkerboard patterns). We characterize these phases via order parameters. In the case of global synchrony, the speed of synchronization depends on the adhesive effects of the clocks. Synchronization happens fastest when cells in opposite phases adhere the strongest ("opposites attract"). When cells of the same clock phase adhere the strongest ("like attracts like"), synchronization is slower. Surprisingly, the slowest synchronization happens in the diffusive mixing case, where cell-cell adhesion is independent of clock phase. We briefly discuss potential applications of the model, such as pattern formation in the auditory sensory epithelium.


Asunto(s)
Trastornos Mentales , Humanos , Adhesión Celular , Difusión , Epitelio
20.
J Vis Exp ; (204)2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38436411

RESUMEN

Women's health, and particularly diseases of the female reproductive tract (FRT), have not received the attention they deserve, even though an unhealthy reproductive system may lead to life-threatening diseases, infertility, or adverse outcomes during pregnancy. One barrier in the field is that there has been a dearth of preclinical, experimental models that faithfully mimic the physiology and pathophysiology of the FRT. Current in vitro and animal models do not fully recapitulate the hormonal changes, microaerobic conditions, and interactions with the vaginal microbiome. The advent of Organ-on-a-Chip (Organ Chip) microfluidic culture technology that can mimic tissue-tissue interfaces, vascular perfusion, interstitial fluid flows, and the physical microenvironment of a major subunit of human organs can potentially serve as a solution to this problem. Recently, a human Vagina Chip that supports co-culture of human vaginal microbial consortia with primary human vaginal epithelium that is also interfaced with vaginal stroma and experiences dynamic fluid flow has been developed. This chip replicates the physiological responses of the human vagina to healthy and dysbiotic microbiomes. A detailed protocol for creating human Vagina Chips has been described in this article.


Asunto(s)
Líquido Extracelular , Vagina , Animales , Embarazo , Humanos , Femenino , Técnicas de Cocultivo , Epitelio , Dispositivos Laboratorio en un Chip
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