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3 Different cytoskeletal structures associated with AJs. The diagram shows three major types of the cytoskeleton that associate with AJs and play important roles in junctional architecture and dynamics. (For color version of this figure, the reader is referred to the online version of this book.)
Source publication
Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by several types of adhesive integral membrane proteins, most notably cadherins and nectins that are clustered and stabilized by a number of cytoplasmic scaffolds. AJs are key regulators of...
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Background/aims:
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Methods:
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Background
Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer’s disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect o...
Citations
... HTTs facilitate Golgi-related vesicular trafficking, and mHTTs impair vesicular trafficking [64,65]. Junctional complexes attach to neighboring progenitors and seal the border of the neuroepithelium, which is critical for spatiotemporal differentiation in neurogenesis [51,66]. Junctional complex proteins are synthesized on the ER, transferred to the cell membrane by clathrin+ vesicles after sorting in the Golgi apparatus, and form new junctional complexes, including TJ, AJ, and gap junctions [66]. ...
... Junctional complexes attach to neighboring progenitors and seal the border of the neuroepithelium, which is critical for spatiotemporal differentiation in neurogenesis [51,66]. Junctional complex proteins are synthesized on the ER, transferred to the cell membrane by clathrin+ vesicles after sorting in the Golgi apparatus, and form new junctional complexes, including TJ, AJ, and gap junctions [66]. The results of ARF1 inhibition in the neural tubes by BFA support the idea that the deficiency of ARF1 recruitment contributes to the junctional complex impairments in NEs of HD-hCOs, consequently altering the corticogenesis in the human fetal brain, which is regulated by a strict spatiotemporal manner [67]. ...
Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington’s disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.
... Intestinal barrier integrity is mediated by TJs and adherens junction proteins [40]. The well-known TJ proteins are occludin, ZO-1, and claudin [41], and adherens junction proteins include cadherin and catenin [42]. Several mechanisms have been reported to be linked with gut barrier loss, such as decreased expression of TJs and adherens junction proteins, claudin switching, and modulation of the cytoskeleton [35]. ...
Objective and Design
Annexin A1 (ANXA1) plays a role in maintaining intestinal hemostasis, especially following mucosal inflammation. The published data about ANXA1 was derived from experimental animal models where there is an overlapping between epithelial and immune cells. There is no in vitro gut epithelial model that can assess the direct effect of ANXA1 on the gut epithelium.
Methods
We developed high-throughput stem-cell-based murine epithelial cells and bacterial lipopolysaccharides (LPS) were used to induce inflammation. The impact of ANXA1 and its functional part (Ac2-26) was evaluated in the inflamed model. Intestinal integrity was assessed by the transepithelial electrical resistance (TEER), and FITC-Dextran permeability. Epithelial junction proteins were assessed using confocal microscopy and RT-qPCR. Inflammatory cytokines were evaluated by RT-qPCR and ELISA.
Results
LPS challenge mediated a damage in the epithelial cells as shown by a drop in the TEER and an increase in FITC-dextran permeability; reduced the expression of epithelial junctional proteins (Occludin, ZO-1, and Cadherin) and increased the expression of the gut leaky protein, Claudin − 2. ANXA1 and Ac2-26 treatment reduced the previous damaging effects. In addition, ANXA1 and Ac2-26 inhibited the inflammatory responses mediated by the LPS and increased the transcription of the anti-inflammatory cytokine, IL-10.
Conclusion
ANXA1 and Ac2-26 directly protect the epithelial integrity by affecting the expression of epithelial junction and inflammatory markers. The inflamed gut model is a reliable tool to study intestinal inflammatory diseases, and to evaluate the efficacy of potential anti-inflammatory drugs and the screening of new drugs that could be candidates for inflammatory bowel disease.
... Surprisingly, as observed in HEK293 cells adapted to suspension [28], cellular component organization pathways associated with cell adhesion such as actin filament-based process, regulation of cell adhesion, apical part of the cell, plasma membrane-bounded cell projection morphogenesis, and extracellular matrix are upregulated via pathway enrichment analysis, while NTA showed an upregulation of the cell adhesion PPI network with CDH18 as its central gene and which can be considered as possible target for engineering in order to improve the cell adaptation to suspension. This upregulation of cell adhesion-related genes could be due to the cells' attempt to restore the attachment to culture surfaces and surrounding cells which could explain the aggregates that are often observed in Vero cell suspension cultures and the cell rings that form on the suspension culture dishes. ...
... The results reported by Ley et al. show that this strategy might be also promising for Vero cells, but a prior, more in-depth genomic analysis for the specific case of Vero cells is necessary before drawing any conclusions. Lastly, the epithelial-to-mesenchymal transition (EMT) pathway is downregulated in Vero cells adapted to suspension, thus highlighting the fact that the adaptation to suspension is not associated with EMT as previously shown with HEK293 cells adapted to suspension [28]. ...
The Vero cell line is the most used continuous cell line for viral vaccine manufacturing. Its anchorage-dependent use renders scaling up challenging and operations very labor-intensive which affects cost effectiveness. Thus, efforts to adapt Vero cells to suspension cultures have been invested, but hurdles such as the long doubling time and low cell viability remain to be addressed. In this study, building on the recently published Vero cell line annotated genome, a functional genomics analysis of the Vero cells adapted to suspension is performed to better understand the genetic and phenotypic switches at play during the adaptation of Vero cells from anchorage-dependent to suspension cultures. Results show downregulation of the epithelial-to-mesenchymal transition (EMT) pathway, highlighting the dissociation between the adaptation to suspension process and EMT. Surprisingly, an upregulation of cell adhesion components is observed, notably the CDH18 gene, the cytoskeleton pathway, and the extracellular pathway. Moreover, a downregulation of the glycolytic pathway is balanced by an upregulation of the asparagine metabolism pathway, promoting cell adaptation to nutrient deprivation. A downregulation of the adherens junctions and the folate pathways alongside with the FYN gene are possible explanations behind the currently observed low-cell viability and long doubling time.
... Transmembrane components of TJs, such as claudins, occludin, and junctional adhesion molecule A (JAM-A), form adhesive bonds with their partners on the opposing cell membrane, whereas on the cytoplasmic side of the membrane, they interact with different scaffolds, most notably members of a 'zonula occludens' (ZO) protein family (5,6). A predominant transmembrane AJ protein, E-cadherin, participates in homotypic interactions with other E-cadherin molecules at the cell surface and makes complexes with cytoplasmic b-catenin, p120-catenin, and a-catenin proteins (7)(8)(9). ...
Disruption of the intestinal epithelial barrier is a hallmark of mucosal inflammation. It increases exposure of the immune system to luminal microbes, triggering a perpetuating inflammatory response. For several decades, the inflammatory stimuli-induced breakdown of the human gut barrier was studied in vitro by using colon cancer derived epithelial cell lines. While providing a wealth of important data, these cell lines do not completely mimic the morphology and function of normal human intestinal epithelial cells (IEC) due to cancer-related chromosomal abnormalities and oncogenic mutations. The development of human intestinal organoids provided a physiologically-relevant experimental platform to study homeostatic regulation and disease-dependent dysfunctions of the intestinal epithelial barrier. There is need to align and integrate the emerging data obtained with intestinal organoids and classical studies that utilized colon cancer cell lines. This review discusses the utilization of human intestinal organoids to dissect the roles and mechanisms of gut barrier disruption during mucosal inflammation. We summarize available data generated with two major types of organoids derived from either intestinal crypts or induced pluripotent stem cells and compare them to the results of earlier studies with conventional cell lines. We identify research areas where the complementary use of colon cancer-derived cell lines and organoids advance our understanding of epithelial barrier dysfunctions in the inflamed gut and identify unique questions that could be addressed only by using the intestinal organoid platforms.
... This complex contains transmembrane proteins, including claudins, occludin, and tricellulin, as well as cytoplasmic plaque proteins, such as zona occludens [2]. AJ is a specific cytoplasmic face linked to the actin cytoskeleton that plays a major role in initiating cell-cell contacts [6][7][8]. AJ consists of a few transmembrane proteins (E-cadherin and nectins) and some intracellular components (p120-catenin, β-catenin, and α-catenin) [9]. ...
Background
Disruptions of the intestinal epithelial barrier (IEB) are frequently observed in various digestive diseases, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). This study assessed the improvement in the IEB during the laxative activity of phlorotannin (Pt) harvested from Ecklonia cava in constipation by examining the changes in the expression of the regulatory proteins for the tight junction (TJ) and adherens junction (AJ), and inflammatory cytokines in Sprague Dawley (SD) rats with loperamide (Lm)-induced constipation after a Pt treatment.
Results
The Pt treatment induced laxative activity, including the improvement of feces-related parameters, gastrointestinal transit rate, and histological structure of the mid colon in Lm-treated SD rats. In addition, significant recovery effects were detected in the histology of IEB, including the mucus layer, epithelial cells, and lamina propria in the mid colon of Lm + Pt treated SD rats. The expression levels of E-cadherin and p120-catenin for AJ and the ZO-1, occludin, and Claudin-1 genes for TJ in epithelial cells were improved remarkably after the Pt treatment, but the rate of increase was different. Furthermore, the Pt treatment increased the expression level of several inflammatory cytokines, such as TNF-α, IL-6, IL-1β, IL-13, and IL-4 in Lm + Pt treated SD rats.
Conclusions
These results provide the first evidence that the laxative activity of Pt in SD rats with Lm-induced constipation phenotypes involve improvements in the IEB.
... They are critical for normal tissue morphogenesis, and their disruption results in pathological abnormalities. 62 The results from our transcriptome analysis showed that a toxic dose of rinse aid could affect the integrity of TJs such as CLDN1, OCLN, CLDN4, CLDN12, and CLDN19 and AJs such as CDH1, which encodes epithelial cadherin, CDH6, CDH11, CTNNA1, and CTNNB1, which encodes catenin alpha and beta 1. The current study results suggested that TJ and AJ integrity disruption induced by rinse aid could arise from a direct effect on the barrier molecules, as well as cellular damage and altered mRNA expressions of some of the TJ and AJ proteins. ...
Background
The increased prevalence of many chronic inflammatory diseases linked to gut epithelial barrier leakiness has prompted us to investigate the role of extensive use of dishwasher detergents, among other factors.
Objective
We sought to investigate the effects of professional and household dishwashers, and rinse agents, on cytotoxicity, barrier function, transcriptome, and protein expression in gastrointestinal epithelial cells.
Methods
Enterocytic liquid-liquid interfaces were established on permeable supports, and direct cellular cytotoxicity, transepithelial electrical resistance, paracellular flux, immunofluorescence staining, RNA-sequencing transcriptome, and targeted proteomics were performed.
Results
The observed detergent toxicity was attributed to exposure to rinse aid in a dose-dependent manner up to 1:20,000 v/v dilution. A disrupted epithelial barrier, particularly by rinse aid, was observed in liquid-liquid interface cultures, organoids, and gut-on-a-chip, demonstrating decreased transepithelial electrical resistance, increased paracellular flux, and irregular and heterogeneous tight junction immunostaining. When individual components of the rinse aid were investigated separately, alcohol ethoxylates elicited a strong toxic and barrier-damaging effect. RNA-sequencing transcriptome and proteomics data revealed upregulation in cell death, signaling and communication, development, metabolism, proliferation, and immune and inflammatory responses of epithelial cells. Interestingly, detergent residue from professional dishwashers demonstrated the remnant of a significant amount of cytotoxic and epithelial barrier–damaging rinse aid remaining on washed and ready-to-use dishware.
Conclusions
The expression of genes involved in cell survival, epithelial barrier, cytokine signaling, and metabolism was altered by rinse aid in concentrations used in professional dishwashers. The alcohol ethoxylates present in the rinse aid were identified as the culprit component causing the epithelial inflammation and barrier damage.
... Heterophilic interactions can also be established, albeit at weaker affinity. For example, E-cadherin can interact with N-cadherin [52,53], which may be neo-expressed in transformed epithelial cells as a consequence of EMT-induced cadherin switch [25,26]. ...
Cell-to-cell adhesion is a key element in epithelial tissue integrity and homeostasis during embryogenesis, response to damage, and differentiation. Loss of cell adhesion and gain of mesenchymal features, a phenomenon known as epithelial to mesenchymal transition (EMT), are essential steps in cancer progression. Interestingly, downregulation or degradation by endocytosis of epithelial adhesion molecules (e.g., E-cadherin) associates with EMT and promotes cell migration. Autophagy is a physiological intracellular degradation and recycling process. In cancer, it is thought to exert a tumor suppressive role in the early phases of cell transformation but, once cells have gained a fully transformed phenotype, autophagy may fuel malignant progression by promoting EMT and conferring drug resistance. In this review, we discuss the crosstalk between autophagy, EMT, and turnover of epithelial cell adhesion molecules, with particular attention to E-cadherin.
... (iv) LFCs resembled an epithelium, which was supported by two findings: (a) the presence of intercellular junctions and (b) the presence of polarized light cells bearing abundant apical microvilli. Adherens junctions are abundant and can establish temporal cell attachments to dynamically coordinate intercellular communication (Ivanov & Naydenov, 2013). Lobo et al. (2003) argued that adherens junctions may play roles in cell aggregation, spheroid compaction, and cell migration in NS. ...
Neurospheres (NS) derived from adult stem cells of non‐neural tissues represent a promising source of neural stem cells (NSCs) and neural progenitor cells (NPCs) for autologous cell therapy. Knowing the fine structure of NS cells is essential for characterizing them during differentiation or oncogenic transformation. NS are generated by culturing ovarian cortical cells (OCCs) under specific conditions. To establish whether these OCCs exhibited a similar morphophenotype as those from the central nervous system (CNS) reported in the literature, sheep OCCs were cultured for 21 days to generate NS. Expression levels of pluripotency (Nanog, octamer‐binding transcription factor 4 [Oct4], and SRY‐box transcription factor 2 [Sox2]) and NSCs/NPCs (nestin, paired box 6 [Pax6], and p75 neurotrophin receptor [P75NTR]) transcripts were analyzed by quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR), the NSC/NPC antigens were immunolocalized, and structural and ultrastructural analyses were performed in OCC‐NS on Days 10, 15, and 21 in culture. Spheroids expressed transcripts and antigens of pluripotency as well as NSCs/NPCs. Cells were arranged into an inner core, with frequent apoptotic and degenerative events, and a peripheral epithelial‐like cover with abundant cytoplasmic organelles, apical microvilli, and filament bundles of cytoskeleton elements. Adherens junctions and apical tight and lateral loose interdigitations were found in peripheral cells that eventually lost apical–basal polarization, which might indicate their disengaging/aggregating from/to the NS. We can conclude that OCC‐NS shares the most structural and ultrastructural characteristics with CNS‐NS.
... These genes are known to be expressed on the endothelium of blood vessels or leukocytes. The adherens junction is a key regulator of tissue architecture and dynamics via control of cell proliferation, motility, and survival 27 . During tissue inflammation, the adherens junction is disrupted 27 . ...
... The adherens junction is a key regulator of tissue architecture and dynamics via control of cell proliferation, motility, and survival 27 . During tissue inflammation, the adherens junction is disrupted 27 . Inflammatory processes, in turn, cannot do without endothelial cell adherens junctions 28 . ...
Background:
Androgenetic alopecia (AGA) leads to thinning of scalp hair and affects 60%~70% of the adult population worldwide. Developing more effective treatments and studying its mechanism are of great significance. Previous clinical studies have revealed that hair growth is stimulated by 650-nm red light.
Objective:
This study aimed to explore the effect and mechanism of 650-nm red light on the treatment of AGA by using ex vivo hair follicle culture.
Methods:
Human hair follicles were obtained from hair transplant patients with AGA. Hair follicles were cultured in Williams E medium and treated with or without 650-nm red light. Real-time RT-PCR and immunofluorescence staining were used to detect the expression level of genes and proteins in hair follicles, respectively. RNA-sequencing analysis was carried out to reveal the distinct gene signatures upon 650 nm treatment.
Results:
Low-level 650 nm red light promoted the proliferation of human hair follicles in the experimental cultured-tissue model. Consistently, 650 nm red light significantly delayed the transition of hair cycle from anagen to catagen in vitro. RNA-seq analysis and gene clustering for the differentially expressed genes suggests that leukocyte transendothelial migration, metabolism, adherens junction and other biological process maybe involved in stimulation of hair follicles by 650-nm red light treatment.
Conclusion:
The effect of 650-nm red light on ex vivo hair follicles and the transcriptome set which implicates the role of red light in promoting hair growth and reversing of miniaturization process of AGA were identified.
... On the other hand, the adherens junction pathway, which regulates cell-cell adhesion and is essential for viability (via the control of cell proliferation, polarity, shape, motility and survival) [21], is downregulated alongside the aspartate metabolic pathway, the mitochondrial 1-carbon metabolic pathway, the MYC and E2F targets pathway, which could explain the low cell density observed during Vero cells adaptation to suspension. ...
The Vero cell line is the most used continuous cell line for viral vaccine manufacturing. Its anchorage-dependent use renders scaling-up challenging and operations very labor intensive which affects cost effectiveness. Thus, efforts to adapt Vero cells to suspension cultures have been invested but hurdles such as the long doubling time and low cell viability remain to be addressed. In this study, building on the recently published Vero cell line annotated genome, a functional genomics analysis of the Vero cells adapted to suspension is performed to better understand the genetic and phenotypic switches at play during the adaptation of Vero cells from anchorage-dependent to suspension cultures. Results show a downregulation of the epithelial to mesenchymal transition (EMT) pathway, highlighting the dissociation between the adaptation to suspension process and EMT. Surprisingly, an upregulation of cell adhesion components is observed, notably the CDH18 gene, the cytoskeleton pathway, and the extracellular pathway. Moreover, a downregulation of the glycolytic pathway are balanced by an upregulation of the asparagine metabolism pathway, promoting cell adaptation to nutrient deprivation. A downregulation of the adherens junctions and the folate pathways alongside with the FYN gene are possible explanations behind the currently observed low cell viability and long doubling time.
