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Cell Jan 2023How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid...
How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.
Topics: Humans; Cilia; COVID-19; Respiratory System; SARS-CoV-2; Microvilli; Virus Internalization; Epithelial Cells
PubMed: 36580912
DOI: 10.1016/j.cell.2022.11.030 -
Experimental Eye Research Feb 2019Human RPE cell lines, especially the ARPE-19 cell line, are widely-used in eye research, as well as general epithelial cell studies. In comparison with primary RPE...
Human RPE cell lines, especially the ARPE-19 cell line, are widely-used in eye research, as well as general epithelial cell studies. In comparison with primary RPE cells, they offer relative convenience and consistency, but cultures derived from these lines are typically not well differentiated. We describe a simple, rapid method to establish cultures from ARPE-19 cells, with significantly improved epithelial cell morphology and cytoskeletal organization, and RPE-related functions. We identify the presence of nicotinamide, a member of the vitamin B family, as an essential factor in promoting the observed differentiation, indicating the importance of metabolism in RPE cell differentiation.
Topics: Bestrophins; Biomarkers; Cell Differentiation; Cell Line; Cytoskeleton; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Humans; Integrin beta Chains; Microvilli; Niacinamide; Occludin; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; Vitamin B Complex; Zonula Occludens-1 Protein; cis-trans-Isomerases
PubMed: 30336127
DOI: 10.1016/j.exer.2018.10.009 -
Methodist DeBakey Cardiovascular Journal 2016Olmesartan-induced enteropathy mimics celiac disease clinically and pathologically. As in celiac disease, the pathologic findings are villous atrophy and increased...
Olmesartan-induced enteropathy mimics celiac disease clinically and pathologically. As in celiac disease, the pathologic findings are villous atrophy and increased intraepithelial lymphocytes. Clinical presentation of olmesartan-induced enteropathy includes diarrhea, weight loss, and nausea. In contrast to celiac disease, tissue transglutaminase is not elevated and there is no response to a gluten-free diet. Including this entity in the differential diagnosis of sprue-like enteropathy is critical for its early diagnosis since replacing olmesartan with an alternative antihypertensive drug can simplify the diagnostic workup and provide both clinical and histologic improvement.
Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrophy; Biopsy; Celiac Disease; Diagnosis, Differential; Diarrhea; Drug Substitution; Female; Humans; Hypertension; Imidazoles; Intestinal Diseases; Intestinal Mucosa; Lymphocytes; Microvilli; Predictive Value of Tests; Tetrazoles; Weight Loss
PubMed: 28289500
DOI: 10.14797/mdcj-12-4-230 -
FEBS Letters Nov 2020Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized... (Review)
Review
Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized cells, where they control cell movement or the generation of fluid flow, whereas immotile primary cilia protrude from the surface of almost every mammalian cell to detect and transduce extracellular signals. Despite these differences, all cilia consist of a microtubule core called the axoneme. Microvilli instead contain bundled linear actin filaments and are mainly localized on epithelial cells, where they modulate the absorption of nutrients. Cilia and microvilli constitute subcellular compartments with distinctive lipid and protein repertoires and specialized functions. Here, we summarize the role of sphingolipids in defining the identity and controlling the function of cilia and microvilli in mammalian cells.
Topics: Animals; Cilia; Humans; Microvilli; Sphingolipids
PubMed: 32415987
DOI: 10.1002/1873-3468.13816 -
The Journal of Clinical Investigation May 2022Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism...
Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.
Topics: Animals; Caco-2 Cells; Diarrhea, Infantile; Facies; Fetal Growth Retardation; Hair Diseases; Humans; Infant; Intracellular Signaling Peptides and Proteins; Malabsorption Syndromes; Microvilli; Mucolipidoses; Myosin Type V; Phenotype; Zebrafish
PubMed: 35575086
DOI: 10.1172/JCI154997 -
Proceedings of the National Academy of... Oct 2022Multiple membrane-shaping and remodeling processes are associated with tetraspanin proteins by yet unknown mechanisms. Tetraspanins constitute a family of proteins with...
Multiple membrane-shaping and remodeling processes are associated with tetraspanin proteins by yet unknown mechanisms. Tetraspanins constitute a family of proteins with four transmembrane domains present in every cell type. Prominent examples are tetraspanin4 and CD9, which are required for the fundamental cellular processes of migrasome formation and fertilization, respectively. These proteins are enriched in curved membrane structures, such as cellular retraction fibers and oocyte microvilli. The factors driving this enrichment are, however, unknown. Here, we revealed that tetraspanin4 and CD9 are curvature sensors with a preference for positive membrane curvature. To this end, we used a biomimetic system emulating membranes of cell retraction fibers and oocyte microvilli by membrane tubes pulled out of giant plasma membrane vesicles with controllable membrane tension and curvature. We developed a simple thermodynamic model for the partitioning of curvature sensors between flat and tubular membranes, which allowed us to estimate the individual intrinsic curvatures of the two proteins. Overall, our findings illuminate the process of migrasome formation and oocyte microvilli shaping and provide insight into the role of tetraspanin proteins in membrane remodeling processes.
Topics: Cell Membrane; Microvilli; Oocytes; Tetraspanin 28; Tetraspanin 29; Tetraspanin 30; Tetraspanins
PubMed: 36252000
DOI: 10.1073/pnas.2208993119 -
Current Biology : CB May 2021Filopodia, microvilli and stereocilia represent an important group of plasma membrane protrusions. These specialized projections are supported by parallel bundles of... (Review)
Review
Filopodia, microvilli and stereocilia represent an important group of plasma membrane protrusions. These specialized projections are supported by parallel bundles of actin filaments and have critical roles in sensing the external environment, increasing cell surface area, and acting as mechanosensors. While actin-associated proteins are essential for actin-filament elongation and bundling in these protrusions, myosin motors have a surprising role in the formation and extension of filopodia and stereocilia and in the organization of microvilli. Actin regulators and specific myosins collaborate in controlling the length of these structures. Myosins can transport cargoes along the length of these protrusions, and, in the case of stereocilia and microvilli, interactions with adaptors and cargoes can also serve to anchor adhesion receptors to the actin-rich core via functionally conserved motor-adaptor complexes. This review highlights recent progress in understanding the diverse roles myosins play in filopodia, microvilli and stereocilia.
Topics: Actins; Microvilli; Myosins; Pseudopodia; Stereocilia
PubMed: 34033792
DOI: 10.1016/j.cub.2021.04.005 -
The Pan African Medical Journal 2018
Topics: Dehydration; Diarrhea; Humans; Hypernatremia; Infant, Newborn; Infant, Premature; Malabsorption Syndromes; Male; Microvilli; Mucolipidoses
PubMed: 30364420
DOI: 10.11604/pamj.2018.30.109.12330 -
Journal of Extracellular Vesicles Sep 2022Cell-cell interactions in the central nervous system are based on the release of molecules mediating signal exchange and providing structural and trophic support through...
Cell-cell interactions in the central nervous system are based on the release of molecules mediating signal exchange and providing structural and trophic support through vesicular exocytosis and the formation of extracellular vesicles. The specific mechanisms employed by each cell type in the brain are incompletely understood. Here, we explored the means of communication used by Müller cells, a type of radial glial cells in the retina, which forms part of the central nervous system. Using immunohistochemical, electron microscopic, and molecular analyses, we provide evidence for the release of distinct extracellular vesicles from endfeet and microvilli of retinal Müller cells in adult mice in vivo. We identify VAMP5 as a Müller cell-specific SNARE component that is part of extracellular vesicles and responsive to ischemia, and we reveal differences between the secretomes of immunoaffinity-purified Müller cells and neurons in vitro. Our findings suggest extracellular vesicle-based communication as an important mediator of cellular interactions in the retina.
Topics: Animals; Ependymoglial Cells; Extracellular Vesicles; Mice; Neuroglia; Neurons; Retina
PubMed: 36043482
DOI: 10.1002/jev2.12254 -
Development (Cambridge, England) Jul 2016The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this... (Review)
Review
The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this extensive surface include generation of an extremely long tube and convolution of the absorptive surface of the tube into villi and microvilli. In this Review, we discuss recent findings regarding the morphogenetic and molecular processes required for intestinal tube elongation and surface convolution, examine shared and unique aspects of these processes in different species, relate these processes to known human maladies that compromise absorptive function and highlight important questions for future research.
Topics: Animals; Humans; Intestinal Absorption; Intestines; Microvilli; Models, Biological; Morphogenesis; Signal Transduction
PubMed: 27381224
DOI: 10.1242/dev.135400