Dataset Information

Cell chirality regulates intercellular junctions and endothelial permeability.

ABSTRACT: Cell chirality is a newly discovered intrinsic property of the cell, reflecting the bias of the cell to polarize in the left-right axis. Despite increasing evidence on its substantial role in the asymmetric development of embryos, little is known about implications of cell chirality in physiology and disease. We demonstrate that cell chirality accounts for the nonmonotonic, dose-response relationship between endothelial permeability and protein kinase C (PKC) activation. The permeability of the endothelial cell layer is tightly controlled in our body, and dysregulation often leads to tissue inflammation and diseases. Our results show that low-level PKC activation is sufficient to reverse cell chirality through phosphatidylinositol 3-kinase/AKT signaling and alters junctional protein organization between cells with opposite chirality, leading to an unexpected substantial change in endothelial permeability. Our findings suggest that cell chirality regulates intercellular junctions in important ways, providing new opportunities for drug delivery across tightly connected semipermeable cellular sheets.

SUBMITTER: Fan J

PROVIDER: S-EPMC6200360 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cell chirality regulates intercellular junctions and endothelial permeability.

Fan Jie J Ray Poulomi P Lu Yao Wei YW Kaur Gurleen G Schwarz John J JJ Wan Leo Q LQ

Science advances 20181024 10

Cell chirality is a newly discovered intrinsic property of the cell, reflecting the bias of the cell to polarize in the left-right axis. Despite increasing evidence on its substantial role in the asymmetric development of embryos, little is known about implications of cell chirality in physiology and disease. We demonstrate that cell chirality accounts for the nonmonotonic, dose-response relationship between endothelial permeability and protein kinase C (PKC) activation. The permeability of the ...[more]

PMID: 30397640

Similar Datasets

Project description:BackgroundThe brain endothelial barrier permeability is governed by tight and adherens junction protein complexes that restrict paracellular permeability at the blood-brain barrier (BBB). Dysfunction of the inter-endothelial junctions has been implicated in neurological disorders such as multiple sclerosis, stroke and Alzheimer's disease. The molecular mechanisms underlying junctional dysfunction during BBB impairment remain elusive. MicroRNAs (miRNAs) have emerged as versatile regulators of the BBB function under physiological and pathological conditions, and altered levels of BBB-associated microRNAs were demonstrated in a number of brain pathologies including neurodegeneration and neuroinflammatory diseases. Among the altered micro-RNAs, miR-27a-3p was found to be downregulated in a number of neurological diseases characterized by loss of inter-endothelial junctions and disruption of the barrier integrity. However, the relationship between miR-27a-3p and tight and adherens junctions at the brain endothelium remains unexplored. Whether miR-27a-3p is involved in regulation of the junctions at the brain endothelium remains to be determined.MethodsUsing a gain-and-loss of function approach, we modulated levels of miR-27a-3p in an in-vitro model of the brain endothelium, key component of the BBB, and examined the resultant effect on the barrier paracellular permeability and on the expression of essential tight and adherens junctions. The mechanisms governing the regulation of junctional proteins by miR-27a-3p were also explored.ResultsOur results showed that miR-27a-3p inhibitor increases the barrier permeability and causes reduction of claudin-5 and occludin, two proteins highly enriched at the tight junction, while miR-27a-3p mimic reduced the paracellular leakage and increased claudin-5 and occludin protein levels. Interestingly, we found that miR-27-3p induces expression of claudin-5 and occludin by downregulating Glycogen Synthase Kinase 3 beta (GSK3ß) and activating Wnt/ß-catenin signaling, a key pathway required for the BBB maintenance.ConclusionFor the first time, we showed that miR-27a-3p is a positive regulator of key tight junction proteins, claudin-5 and occludin, at the brain endothelium through targeting GSK3ß gene and activating Wnt/ß-catenin signaling. Thus, miR-27a-3p may constitute a novel therapeutic target that could be exploited to prevent BBB dysfunction and preserves its integrity in neurological disorders characterized by impairment of the barrier's function.

Dataset Information

Cell chirality regulates intercellular junctions and endothelial permeability.

Publications

Cell chirality regulates intercellular junctions and endothelial permeability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets