Tissue Barriers最新文献

{"title":"Mucosal p-STAT1/3 correlates with histologic disease activity in Crohn's disease and is responsive to filgotinib.","authors":"Walter Reinisch,&nbsp;Adrian Serone,&nbsp;Xavier Hébuterne,&nbsp;Tanja Kühbacher,&nbsp;Maria Kłopocka,&nbsp;Xavier Roblin,&nbsp;Jens Brodbeck,&nbsp;Kim Etchevers,&nbsp;René Galien,&nbsp;Ethan Grant,&nbsp;Chantal Tasset,&nbsp;Oh Kyu Yoon,&nbsp;Shiva Zaboli,&nbsp;Séverine Vermeire","doi":"10.1080/21688370.2022.2088961","DOIUrl":"https://doi.org/10.1080/21688370.2022.2088961","url":null,"abstract":"<p><p>The validity and relevance of histologic disease activity in Crohn's disease (CD) is unclear, owing to disconnects with endoscopic pathology. Here, we explore relationships between endoscopic, histologic, and molecular activity. This post hoc analysis of the Phase 2 FITZROY trial (NCT02048618) assessed baseline and week 10 (W10) inflammation across matched ileal and colonic segments in CD patients receiving filgotinib 200 mg (n = 42) vs placebo (n = 18). Macroscopic and microscopic disease were assessed by Simple Endoscopic Score for CD ulceration subscore (uSES-CD) and Global Histologic Activity Score activity subscore (aGHAS), respectively. Molecular activity was quantified by phosphorylated signal transducer and activator of transcription (pSTAT)1 and pSTAT3 in epithelium and nonepithelium. Segments were classified as \"low\" or \"high\" activity; correlations and concordance were calculated. Logistic regression identified W10 outcome predictors. Overall, 300 segments in 60 patients were assessed. Baseline uSES-CD and aGHAS correlations were 0.72 and 0.53 in colon and ileum, respectively. pSTAT levels had poor-to-moderate concordance with uSES-CD (κ range, 0.11-0.49) but moderate-to-good concordance with aGHAS (0.43-0.77). With filgotinib vs placebo, uSES-CD and aGHAS decreased in significantly more segments with high baseline uSES-CD and aGHAS, and significantly more segments with high baseline pSTAT improved at W10. pSTAT1 was more sensitive to change than uSES-CD and aGHAS. Low baseline pSTAT3 in colon nonepithelium predicted W10 low uSES-CD (<i>P</i> = .044). There was better concordance between histologic and molecular disease activity associated with higher sensitivity to change vs endoscopic severity in ileocolonic CD. Our results suggest histologic activity be included in the assessment of CD inflammatory burden.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5b/8e/KTIB_11_2088961.PMC10161938.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9685893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical roles of adherens junctions in diseases of the oral mucosa.","authors":"Christina Kingsley, Antonis Kourtidis","doi":"10.1080/21688370.2022.2084320","DOIUrl":"10.1080/21688370.2022.2084320","url":null,"abstract":"<p><p>The oral cavity is directly exposed to a variety of environmental stimuli and contains a diverse microbiome that continuously interacts with the oral epithelium. Therefore, establishment and maintenance of the barrier function of the oral mucosa is of paramount importance for its function and for the body's overall health. The adherens junction is a cell-cell adhesion complex that is essential for epithelial barrier function. Although a considerable body of work has associated barrier disruption with oral diseases, the molecular underpinnings of these associations have not been equally investigated. This is critical, since adherens junction components also possess significant signaling roles in the cell, in addition to their architectural ones. Here, we summarize current knowledge involving adherens junction components in oral pathologies, such as cancer and oral pathogen-related diseases, while we also discuss gaps in the knowledge and opportunities for future investigation of the relationship between adherens junctions and oral diseases.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161952/pdf/KTIB_11_2084320.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9684394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tight junctions: from molecules to gastrointestinal diseases.","authors":"Aekkacha Moonwiriyakit,&nbsp;Nutthapoom Pathomthongtaweechai,&nbsp;Peter R Steinhagen,&nbsp;Papasara Chantawichitwong,&nbsp;Wilasinee Satianrapapong,&nbsp;Pawin Pongkorpsakol","doi":"10.1080/21688370.2022.2077620","DOIUrl":"https://doi.org/10.1080/21688370.2022.2077620","url":null,"abstract":"<p><p>Intestinal epithelium functions as a tissue barrier to prevent interaction between the internal compartment and the external milieu. Intestinal barrier function also determines epithelial polarity for the absorption of nutrients and the secretion of waste products. These vital functions require strong integrity of tight junction proteins. In fact, intestinal tight junctions that seal the paracellular space can restrict mucosal-to-serosal transport of hostile luminal contents. Tight junctions can form both an absolute barrier and a paracellular ion channel. Although defective tight junctions potentially lead to compromised intestinal barrier and the development and progression of gastrointestinal (GI) diseases, no FDA-approved therapies that recover the epithelial tight junction barrier are currently available in clinical practice. Here, we discuss the impacts and regulatory mechanisms of tight junction disruption in the gut and related diseases. We also provide an overview of potential therapeutic targets to restore the epithelial tight junction barrier in the GI tract.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161963/pdf/KTIB_11_2077620.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9689807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coenzyme Q10 protects against doxorubicin-induced cardiomyopathy via antioxidant and anti-apoptotic pathway.","authors":"Dalia A Shabaan,&nbsp;Nora Mostafa,&nbsp;Manal M El-Desoky,&nbsp;Eetmad A Arafat","doi":"10.1080/21688370.2021.2019504","DOIUrl":"https://doi.org/10.1080/21688370.2021.2019504","url":null,"abstract":"<p><p>Doxorubicin (Dox) is an anthracycline antibiotic that treats a variety of malignancies. Unfortunately, its cardiotoxicity limits its therapeutic usefulness. Coenzyme Q10 (CoQ10) has effectively treated and prevented various cardiac diseases and toxicities. This study aimed to evaluate the possible antioxidative and anti-apoptotic cardioprotective effects of CoQ10 against doxorubicin-induced histopathological and molecular changes in cardiomyocytes. Twenty-eight adult Wistar rats were divided into positive control, negative control, Dox-treated group, and Dox+CoQ10-treated. On the 16th day after the start of treatment, the hearts of all rats were dissected, and the left ventricles were processed for histological evaluation; immunohistochemical staining with caspase-3 and inducible nitric oxide synthase (iNOS); ultrastructural examination of cardiomyocytes; molecular assessment of proapoptotic gene Bax and anti-apoptotic gene expression Bcl-2; and biochemical study of malondialdehyde (MDA). The Dox-treated group had disorganized cardiomyocytes with increased interstitial space, vacuolated cytoplasm, and multiple small-sized pyknotic nuclei. A significant increase in caspase-3 and iNOS immunoexpression was observed. Ultrastructurally, the mitochondria were large with abnormal shapes, vacuolated cytoplasm, multiple vacuoles and autophagosomes, collagen fibril accumulation, and multiple small hyperchromatic nuclei. The intercalated discs were disorganized with loss of desmosome junction. The cardiomyocytes also showed significantly increased MDA levels and upregulation of Bax/Bcl-2 gene expression ratio. Co-administration of CoQ10 resulted in significant improvement in the histopathological picture, with a significant decrease in caspase-3 and iNOS immunoexpression and downregulation of the Bax/Bcl-2 gene expression ratio. In conclusion, CoQ10 protects against Dox-induced cardiotoxicity through the regulation of proapoptotic and anti-apoptotic gene expression.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870010/pdf/KTIB_11_2019504.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10609017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The therapeutic prospect of zinc oxide nanoparticles in experimentally induced diabetic nephropathy.","authors":"Samia A Abd El-Baset,&nbsp;Nehad F Mazen,&nbsp;Rehab S Abdul-Maksoud,&nbsp;Asmaa A A Kattaia","doi":"10.1080/21688370.2022.2069966","DOIUrl":"https://doi.org/10.1080/21688370.2022.2069966","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is the most frequent cause of end-stage renal failure. Zinc oxide nanoparticles (ZnO-NPs) are promising antidiabetic agents. Our aim was to evaluate the prospective efficacy of ZnO-NPs in treating DN in streptozotocin-induced diabetic rats. Rats were randomly dispersed into three sets: control group, DN group and DN + ZnO-NPs group. ZnO-NPs were given at a dose of 10 mg/kg/day by oral gavage for 4 weeks. Urine and blood samples were processed for biochemical analyses. Kidney samples were managed for light and electron microscopy studies. Immune histochemical staining of P53, aquaporin11 (AQP11) and mechanistic target of rapamycin (mTOR) were performed. Gene analyses of nephrin, podocin, beclin-1, LC3 and p62 were done. Administration of ZnO-NPs ameliorated the functional and histopathological alterations of the kidney in a rat model of diabetic nephropathy. ZnO-NPs retained the constancy of the glomerular filtration barrier and restored almost normal renal structure. This was confirmed by upregulation of mRNA expression of podocyte markers (nephrin and podocin) and AQP11 immune histochemical expression in the renal tubules. The beneficial outcomes of ZnO-NPs might be attributed to activation of autophagy through inhibiting mTOR signaling pathway. ZnO-NPs enhanced beclin-1 and LC3 mRNA expressions and reduced p62 mRNA expression. ZnO-NPs also exerted anti-apoptotic potential (evidenced by the decrease in p53 immune expression), anti-inflammatory and anti-oxidant effect [endorsed by suppression of serum cyclooxygenase-2 (COX-2) enzyme activity, tissue nuclear factor kappa beta (NF-κB) level and blood hypoxia-inducible factors (HIF-1α) level]. These results may point the way to an effective therapy of DN.Abbreviations: AQP11 Aquaporin11; BUN: Blood urea nitrogen; COX-2: Cyclooxygenase-2; DAB: 3, 3'-diaminobenzidine; DM: Diabetes mellitus; DN: Diabetic nephropathy; ELISA: Enzyme-linked immunosorbent assay; H&E: Hematoxylin & eosin; HIF-1α: Hypoxia-inducible factors; iNOS: inducible nitric oxide synthase; LC3: Microtubule-associated protein 1 light chain 3; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa beta; NPs: Nanoparticles; PAS: Periodic acid Schiff; PCR: Polymerase chain reaction; PGE2: Prostaglandin E2; ROS: Reactive oxygen species; STZ: Streptozotocin; X ± SEM: Mean ± standard error of means; Zn: Zinc; ZnO-NPs: Zinc oxide nanoparticles.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870014/pdf/KTIB_11_2069966.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9457771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GRP75 as a functional element of cholix transcytosis.","authors":"Keyi Liu,&nbsp;Tom Hunter,&nbsp;Alistair Taverner,&nbsp;Kevin Yin,&nbsp;Julia MacKay,&nbsp;Kate Colebrook,&nbsp;Morgan Correia,&nbsp;Amandine Rapp,&nbsp;Randall J Mrsny","doi":"10.1080/21688370.2022.2039003","DOIUrl":"https://doi.org/10.1080/21688370.2022.2039003","url":null,"abstract":"<p><p>Cholix (Chx) is secreted by non-pandemic strains of <i>Vibrio cholerae</i> in the intestinal lumen. For this exotoxin to induce cell death in non-polarized cells in the intestinal lamina propria, it must traverse the epithelium in the fully intact form. We identified host cell elements in polarized enterocytes associated with Chx endocytosis and apical to basal (A→B) vesicular transcytosis. This pathway overcomes endogenous mechanisms of apical vesicle recycling and lysosomal targeting by interacting with several host cell proteins that include the 75 kDa glucose-regulated protein (GRP75). Apical endocytosis of Chx appears to involve the single membrane spanning protein TMEM132A, and interaction with furin before it engages GRP75 in apical vesicular structures. Sorting within these apical vesicles results in Chx being trafficked to the basal region of cells in association with the Lectin, Mannose Binding 1 protein LMAN1. In this location, Chx interacts with the basement membrane-specific heparan sulfate proteoglycan perlecan in recycling endosomes prior to its release from this basal vesicular compartment to enter the underlying lamina propria. While the furin and LMAN1 elements of this Chx transcytosis pathway undergo cellular redistribution that are reflective of the polarity shifts noted for coatamer complexes COPI and COPII, GRP75 and perlecan fail to show these dramatic rearrangements. Together, these data define essential steps in the A→B transcytosis pathway accessed by Chx to reach the intestinal lamina propria where it can engage and intoxicate certain non-polarized cells.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c6/df/KTIB_11_2039003.PMC9870019.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10599377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A host-gut microbial amino acid co-metabolite, <i>p</i>-cresol glucuronide, promotes blood-brain barrier integrity <i>in vivo</i>.","authors":"Andrew V Stachulski,&nbsp;Tobias B-A Knausenberger,&nbsp;Sita N Shah,&nbsp;Lesley Hoyles,&nbsp;Simon McArthur","doi":"10.1080/21688370.2022.2073175","DOIUrl":"https://doi.org/10.1080/21688370.2022.2073175","url":null,"abstract":"<p><p>The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to <i>p</i>-cresol by gut microbes, and then to <i>p</i>-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain <i>in vitro</i> and <i>in vivo</i>. Male C57Bl/6 J mice were used to assess blood-brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut-brain axis.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9177591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transmigration of macrophages through primary adult rat Sertoli cells.","authors":"Hassan Kabbesh,&nbsp;Muhammad A Riaz,&nbsp;Alexandra D Jensen,&nbsp;Georgios Scheiner-Bobis,&nbsp;Lutz Konrad","doi":"10.1080/21688370.2022.2064179","DOIUrl":"https://doi.org/10.1080/21688370.2022.2064179","url":null,"abstract":"<p><p>The blood testis barrier (BTB) is often studied with isolated immature Sertoli cells (SCs), transepithelial resistance (TER) measurements and FITC dextran diffusion assays. Recently, it was found that even in the absence of SCs, only few immune cells enter the seminiferous tubules. Thus, in this study, we evaluated the testicular immunological barrier (TIB) <i>in vitro</i> by transmigration of macrophages through SCs with and without peritubular cells (PCs) and with or without matrigel (MG). Primary PCs were isolated from adult rat testis and kept in mono- or co-cultures with the conditionally reprogrammed primary adult Sertoli cell line (PASC1) from rat that has been recently generated by our group. Rat monocytes isolated from fresh blood were differentiated into M0 macrophages, and after polarization to M1 or M2 macrophages characterized by gene expression of CXCL11 and TNF-α for M1, or CCL17 and CCL22 for M2. Transmigration of LeukoTracker-labeled M0, M1, and M2 macrophages through mono- and co-cultures of PCs/SCs with and without MG demonstrated that SCs are the main constituent of the TIB <i>in vitro</i> with only a negligible contribution of PCs or MG. Moreover, M2 macrophages showed less migration activity compared to M0 or M1. Treatment of SCs with testosterone (T) showed positive effects on the barrier in contrast to negative effects by interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α). The new transmigration model is suitable to evaluate transmigration of macrophages through a barrier consisting of testicular cells and can be applied to study the integrity of testicular barriers with respect to immunological aspects.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870002/pdf/KTIB_11_2064179.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9683112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship of a peptide permeation enhancer.","authors":"Joël Brunner,&nbsp;Gerrit Borchard","doi":"10.1080/21688370.2022.2060692","DOIUrl":"https://doi.org/10.1080/21688370.2022.2060692","url":null,"abstract":"<p><p>The pentapeptide L-R5 has previously been shown to transiently increase the permeability of nasal epithelial cell layers <i>in vitro</i>, allowing paracellular transport of molecules of up to 4 kDa. Protein kinase C zeta (PKC ζ), a member of a family of serine/threonine kinases was shown to be involved in tight junction modulation induced by L-R5. We show here that the ability of L-R5 to modulate tight junctions is comparable to other permeability enhancers such as bilobalide, latrunculin A or C₁₀. Interaction of the peptide with the target protein occurs via electrostatic interaction, with the presence of positive charges being essential for its functionality. L-R5 is myristoylated to allow quick cell entry and onset of activity. While no epithelial cytotoxicity was detected, the hydrophobic myristoyl rest was shown to cause haemolysis. Taken together, these data show that a structural optimization of L-R5 may be possible, both from a toxicological and an efficacy point of view.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/76/KTIB_11_2060692.PMC9870020.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10599382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Desmosomes undergo dynamic architectural changes during assembly and maturation.","authors":"Reena R Beggs,&nbsp;Tejeshwar C Rao,&nbsp;William F Dean,&nbsp;Andrew P Kowalczyk,&nbsp;Alexa L Mattheyses","doi":"10.1080/21688370.2021.2017225","DOIUrl":"https://doi.org/10.1080/21688370.2021.2017225","url":null,"abstract":"<p><p>Desmosomes are macromolecular cell-cell junctions critical for maintaining adhesion and resisting mechanical stress in epithelial tissue. Desmosome assembly and the relationship between maturity and molecular architecture are not well understood. To address this, we employed a calcium switch assay to synchronize assembly followed by quantification of desmosome nanoscale organization using direct Stochastic Optical Reconstruction Microscopy (dSTORM). We found that the organization of the desmoplakin rod/C-terminal junction changed over the course of maturation, as indicated by a decrease in the plaque-to-plaque distance, while the plaque length increased. In contrast, the desmoplakin N-terminal domain and plakoglobin organization (plaque-to-plaque distance) were constant throughout maturation. This structural rearrangement of desmoplakin was concurrent with desmosome maturation measured by E-cadherin exclusion and increased adhesive strength. Using two-color dSTORM, we showed that while the number of individual E-cadherin containing junctions went down with the increasing time in high Ca²⁺, they maintained a wider desmoplakin rod/C-terminal plaque-to-plaque distance. This indicates that the maturation state of individual desmosomes can be identified by their architectural organization. We confirmed these architectural changes in another model of desmosome assembly, cell migration. Desmosomes in migrating cells, closest to the scratch where they are assembling, were shorter, E-cadherin enriched, and had wider desmoplakin rod/C-terminal plaque-to-plaque distances compared to desmosomes away from the wound edge. Key results were demonstrated in three cell lines representing simple, transitional, and stratified epithelia. Together, these data suggest that there is a set of architectural programs for desmosome maturation, and we hypothesize that desmoplakin architecture may be a contributing mechanism to regulating adhesive strength.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c3/16/KTIB_10_2017225.PMC9621066.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39661369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}