Cell chirality regulates intercellular junctions and endothelial permeability

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.