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Biochimica Et Biophysica Acta.... Aug 2023Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their... (Review)
Review
Membrane trafficking is essential to maintain the spatiotemporal control of protein and lipid distribution within membrane systems of eukaryotic cells. To achieve their functional destination proteins are sorted and transported into lipid carriers that construct the secretory and endocytic pathways. It is an emerging theme that lipid diversity might exist in part to ensure the homeostasis of these pathways. Sphingolipids, a chemical diverse type of lipids with special physicochemical characteristics have been implicated in the selective transport of proteins. In this review, we will discuss current knowledge about how sphingolipids modulate protein trafficking through the endomembrane systems to guarantee that proteins reach their functional destination and the proposed underlying mechanisms.
Topics: Sphingolipids; Biological Transport; Protein Transport; Membranes
PubMed: 37201864
DOI: 10.1016/j.bbalip.2023.159334 -
Journal of the American Society of... Nov 2021Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial...
BACKGROUND
Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies.
METHODS
Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB.
RESULTS
Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner.
CONCLUSIONS
Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.
Topics: Animals; Antigen-Antibody Complex; Autoantigens; Cells, Cultured; Coculture Techniques; Endothelial Cells; Exosomes; Extracellular Matrix Proteins; Gene Expression Regulation; Gene Targeting; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Gold Sodium Thiosulfate; Humans; Kidney Glomerulus; Metal Nanoparticles; Mice; MicroRNAs; Paracrine Communication; Permeability; Podocytes; Proteinuria; Transfection; Zebrafish; Zebrafish Proteins
PubMed: 34716242
DOI: 10.1681/ASN.2020121699 -
Biomolecules May 2021Post-surgical adhesions are internal scar tissue and a major health and economic burden. Adhesions affect and involve the peritoneal lining of the abdominal cavity,... (Review)
Review
Post-surgical adhesions are internal scar tissue and a major health and economic burden. Adhesions affect and involve the peritoneal lining of the abdominal cavity, which consists of a continuous mesothelial covering of the cavity wall and majority of internal organs. Our understanding of the full pathophysiology of adhesion formation is limited by the fact that the mechanisms regulating normal serosal repair and regeneration of the mesothelial layer are still being elucidated. Emerging evidence suggests that mesothelial cells do not simply form a passive barrier but perform a wide range of important regulatory functions including maintaining a healthy peritoneal homeostasis as well as orchestrating events leading to normal repair or pathological outcomes following injury. Here, we summarise recent advances in our understanding of serosal repair and adhesion formation with an emphasis on molecular mechanisms and novel gene expression signatures associated with these processes. We discuss changes in mesothelial biomolecular marker expression during peritoneal development, which may help, in part, to explain findings in adults from lineage tracing studies using experimental adhesion models. Lastly, we highlight examples of where local tissue specialisation may determine a particular response of peritoneal cells to injury.
Topics: Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genetic Markers; Humans; Peritoneum; Tissue Adhesions
PubMed: 34063089
DOI: 10.3390/biom11050692 -
Nature Communications Dec 2023PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are...
PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA cells. Sub-epithelial PDGFRA myofibroblasts are principal sources of BMP ligands and two molecularly distinct pools distribute asymmetrically along antral glands but together fail to support epithelial growth in vitro. In contrast, PDGFRA CD55 cells strategically positioned beneath gastric glands promote epithelial expansion in the absence of other cells or factors. This population encompasses a small fraction expressing the BMP antagonist Grem1. Although Grem1 cell ablation in vivo impairs intestinal stem cells, gastric stem cells are spared, implying that CD55 cell activity in epithelial self-renewal derives from other subpopulations. Our findings shed light on spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for epithelial support.
Topics: Mice; Animals; Stomach; Gastric Mucosa; Stem Cells; Intestines; Pyloric Antrum; Receptor Protein-Tyrosine Kinases; Epithelial Cells
PubMed: 38042929
DOI: 10.1038/s41467-023-43619-y -
Mucosal Immunology Sep 2021The airway epithelium protects us from environmental insults, which we encounter with every breath. Not only does it passively filter large particles, it also senses... (Review)
Review
The airway epithelium protects us from environmental insults, which we encounter with every breath. Not only does it passively filter large particles, it also senses potential danger and alerts other cells, including immune and nervous cells. Together, these tissues orchestrate the most appropriate response, balancing the need to eliminate the danger with the risk of damage to the host. Each cell subset within the airway epithelium plays its part, and when impaired, may contribute to the development of respiratory disease. Here we highlight recent advances regarding the cellular and functional heterogeneity along the airway epithelium and discuss how we can use this knowledge to design more effective, targeted therapeutics.
Topics: Animals; Biological Variation, Population; Biomarkers; Disease Susceptibility; Drug Development; Epithelial Cells; Gene Expression Regulation; Homeostasis; Host-Pathogen Interactions; Humans; Immunity, Mucosal; Molecular Targeted Therapy; Respiratory Mucosa; Signal Transduction
PubMed: 33608655
DOI: 10.1038/s41385-020-00370-7 -
BMC Biology Dec 2023Olfactory sensory neurons detect odourants via multiple long cilia that protrude from their dendritic endings. The G protein-coupled receptor GPRC5C was identified as...
BACKGROUND
Olfactory sensory neurons detect odourants via multiple long cilia that protrude from their dendritic endings. The G protein-coupled receptor GPRC5C was identified as part of the olfactory ciliary membrane proteome, but its function and localization is unknown.
RESULTS
High-resolution confocal and electron microscopy revealed that GPRC5C is located at the base of sensory cilia in olfactory neurons, but not in primary cilia of immature neurons or stem cells. Additionally, GPRC5C localization in sensory cilia parallels cilia formation and follows the formation of the basal body. In closer examination, GPRC5C was found in the ciliary transition zone. GPRC5C deficiency altered the structure of sensory cilia and increased ciliary layer thickness. However, primary cilia were unaffected. Olfactory sensory neurons from Gprc5c-deficient mice exhibited altered localization of olfactory signalling cascade proteins, and of ciliary phosphatidylinositol-4,5-bisphosphat. Sensory neurons also exhibited increased neuronal activity as well as altered mitochondrial morphology, and knockout mice had an improved ability to detect food pellets based on smell.
CONCLUSIONS
Our study shows that GPRC5C regulates olfactory cilia composition and length, thereby controlling odour perception.
Topics: Animals; Mice; Cilia; Mice, Knockout; Odorants; Olfactory Receptor Neurons; Receptors, G-Protein-Coupled; Smell
PubMed: 38110903
DOI: 10.1186/s12915-023-01790-0 -
Philosophical Transactions of the Royal... Dec 2022Embryonic development and growth in placental mammals proceeds with the support of exchanges of gases, nutrients and waste products between maternal tissues and... (Review)
Review
Embryonic development and growth in placental mammals proceeds with the support of exchanges of gases, nutrients and waste products between maternal tissues and offspring. Murine embryos are surrounded by several extraembryonic membranes, parietal and visceral yolk sacs, and amnion in the uterus. Notably, the parietal yolk sac is the most outer membrane, consists of three layers, trophoblasts and parietal endoderm (PaE) cells, and is separated by a thick basal lamina termed Reichert's membrane (RM). RM is composed of extracellular matrix (ECM) initially formed as the basement membrane of the trophectoderm of pre-implanted embryos and followed by the heavy deposition of ECM mainly produced in PaE cells of post-implanted embryos. In addition to the physiological roles of RM, such as gas and nutrient exchange, it also plays a crucial role in cushioning and dispersing intrauterine pressures exerted on embryos for normal egg-cylinder morphogenesis. Mechanistically, such intrauterine pressures generated by uterine smooth muscle contractions appear to be involved in the elongation of the egg-cylinder shape, along with primary axis formation, as an important biomechanical element . This review focuses on our current views of the roles of RM in properly buffering intrauterine mechanical forces for mouse egg-cylinder morphogenesis. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.
Topics: Animals; Basement Membrane; Endoderm; Female; Gases; Mammals; Mice; Placenta; Pregnancy; Waste Products; Yolk Sac
PubMed: 36252218
DOI: 10.1098/rstb.2021.0257 -
American Journal of Physiology. Renal... Dec 2023The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been... (Review)
Review
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of , resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
Topics: Mice; Humans; Animals; Nephrosis, Lipoid; Podocytes; Common Cold; Proteinuria; Glomerular Basement Membrane; Recurrence; Nephrotic Syndrome; Transcription Factors; Homeodomain Proteins
PubMed: 37795536
DOI: 10.1152/ajprenal.00219.2023 -
Philosophical Transactions of the Royal... Dec 2022In amniotic vertebrates (birds, reptiles and mammals), an extraembryonic structure called the chorioallantoic membrane (CAM) functions as respiratory organ for embryonic...
In amniotic vertebrates (birds, reptiles and mammals), an extraembryonic structure called the chorioallantoic membrane (CAM) functions as respiratory organ for embryonic development. The CAM is derived from fusion between two pre-existing membranes, the allantois, a hindgut diverticulum and a reservoir for metabolic waste, and the chorion which marks the embryo's external boundary. Modified CAM in eutherian mammals, including humans, gives rise to chorioallantoic placenta. Despite its importance, little is known about cellular and molecular mechanisms mediating CAM formation and maturation. In this work, using the avian model, we focused on the early phase of CAM morphogenesis when the allantois and chorion meet and initiate fusion. We report here that chicken chorioallantoic fusion takes place when the allantois reaches the size of 2.5-3.0 mm in diameter and in about 6 hours between E3.75 and E4. Electron microscopy and immunofluorescence analyses suggested that before fusion, in both the allantois and chorion, an epithelial-shaped mesothelial layer is present, which dissolves after fusion, presumably by undergoing epithelial-mesenchymal transition. The fusion process , however, is independent of allantoic growth, circulation, or its connection to the developing mesonephros. Mesoderm cells derived from the allantois and chorion can intermingle post-fusion, and chorionic ectoderm cells exhibit a specialized sub-apical intercellular interface, possibly to facilitate infiltration of allantois-derived vascular progenitors into the chorionic ectoderm territory for optimal oxygen transport. Finally, we investigated chorioallantoic fusion-like process in primates, with limited numbers of archived human and fresh macaque samples. We summarize the similarities and differences of CAM formation among different amniote groups and propose that mesothelial epithelial-mesenchymal transition mediates chorioallantoic fusion in most amniotic vertebrates. Further study is needed to clarify tissue morphogenesis leading to chorioallantoic fusion in primates. Elucidating molecular mechanisms regulating mesothelial integrity and epithelial-mesenchymal transition will also help understand mesothelial diseases in the adult, including mesothelioma, ovarian cancer and fibrosis. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.
Topics: Allantois; Animals; Chorioallantoic Membrane; Chorion; Epithelium; Humans; Mammals; Oxygen
PubMed: 36252211
DOI: 10.1098/rstb.2021.0263 -
Nutrients Dec 2020Primary eosinophilic gastrointestinal disorders (EGIDs) are emerging chronic/remittent inflammatory diseases of unknown etiology, which may involve any part of the... (Review)
Review
Primary eosinophilic gastrointestinal disorders (EGIDs) are emerging chronic/remittent inflammatory diseases of unknown etiology, which may involve any part of the gastrointestinal (GI) tract, in the absence of secondary causes of GI eosinophilia. Eosinophilic esophagitis is the prototype of eosinophilic gastrointestinal disorders and is clinically characterized by symptoms related to esophageal inflammation and dysfunction. A few studies have assessed the nutritional status of patients with eosinophilic gastrointestinal disorders, showing conflicting results. This review summarizes the current evidence on the nutritional status of patients with EGIDs, focusing on the pediatric point of view and also speculating potential etiological mechanisms.
Topics: Adult; Age Factors; Child; Enteritis; Eosinophilia; Eosinophilic Esophagitis; Esophageal Mucosa; Gastric Mucosa; Gastritis; Humans; Intestinal Mucosa; Malnutrition; Nutritional Status
PubMed: 33396413
DOI: 10.3390/nu13010128