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1.
bioRxiv ; 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38313256

ABSTRACT

Glioblastoma (GBM) is a malignant brain tumor with uncontrolled invasive growth. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 to gain biomechanical plasticity for polarized migration through confined space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal active endocytosis at cell front and filamentous actin assembly at rear to propel GBM cells through constrictions. These two processes are interconnected and governed by Plexin-B2 that orchestrates cortical actin and membrane tension, shown by biomechanical assays. Molecular dynamics simulations predict that balanced membrane and actin tension are required for optimal migratory velocity and consistency. Furthermore, Plexin-B2 mechanosensitive function requires a bendable extracellular ring structure and affects membrane internalization, permeability, phospholipid composition, as well as inner membrane surface charge. Together, our studies unveil a key element of membrane tension and mechanoelectrical coupling via Plexin-B2 that enables GBM cells to adapt to physical constraints and achieve polarized confined migration.

2.
Nat Commun ; 12(1): 6019, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34650052

ABSTRACT

During morphogenesis, molecular mechanisms that orchestrate biomechanical dynamics across cells remain unclear. Here, we show a role of guidance receptor Plexin-B2 in organizing actomyosin network and adhesion complexes during multicellular development of human embryonic stem cells and neuroprogenitor cells. Plexin-B2 manipulations affect actomyosin contractility, leading to changes in cell stiffness and cytoskeletal tension, as well as cell-cell and cell-matrix adhesion. We have delineated the functional domains of Plexin-B2, RAP1/2 effectors, and the signaling association with ERK1/2, calcium activation, and YAP mechanosensor, thus providing a mechanistic link between Plexin-B2-mediated cytoskeletal tension and stem cell physiology. Plexin-B2-deficient stem cells exhibit premature lineage commitment, and a balanced level of Plexin-B2 activity is critical for maintaining cytoarchitectural integrity of the developing neuroepithelium, as modeled in cerebral organoids. Our studies thus establish a significant function of Plexin-B2 in orchestrating cytoskeletal tension and cell-cell/cell-matrix adhesion, therefore solidifying the importance of collective cell mechanics in governing stem cell physiology and tissue morphogenesis.


Subject(s)
Actomyosin/metabolism , Cell Adhesion/physiology , Cytoskeleton/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Stem Cells/metabolism , Actins , CRISPR-Cas Systems , Cell Differentiation , Cell-Matrix Junctions/metabolism , Embryonic Stem Cells , Gene Editing , Gene Expression , Humans , Mechanotransduction, Cellular , Morphogenesis , Neural Stem Cells , Semaphorins , Signal Transduction
3.
Kidney Int ; 96(4): 957-970, 2019 10.
Article in English | MEDLINE | ID: mdl-31402170

ABSTRACT

Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-ß receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.


Subject(s)
Albuminuria/pathology , Cell Communication/drug effects , Endothelial Cells/pathology , Kidney Glomerulus/pathology , Receptor, Endothelin A/metabolism , Albuminuria/chemically induced , Albuminuria/drug therapy , Albuminuria/genetics , Animals , Capillaries/cytology , Capillaries/drug effects , Capillaries/pathology , Capillaries/ultrastructure , Disease Models, Animal , Doxorubicin/toxicity , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelin A Receptor Antagonists/administration & dosage , Endothelin B Receptor Antagonists/administration & dosage , Endothelin-1/metabolism , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Endothelium, Vascular/ultrastructure , Humans , Kidney Glomerulus/blood supply , Kidney Glomerulus/cytology , Kidney Glomerulus/drug effects , Mice , Mice, Transgenic , Microscopy, Electron, Scanning , Mitochondria/drug effects , Mitochondria/metabolism , Podocytes/cytology , Podocytes/drug effects , Podocytes/metabolism , Podocytes/pathology , Reactive Oxygen Species/metabolism , Receptor, Endothelin B/metabolism , Receptor, Transforming Growth Factor-beta Type I/genetics , Receptor, Transforming Growth Factor-beta Type I/metabolism
4.
Nat Commun ; 10(1): 2061, 2019 05 03.
Article in English | MEDLINE | ID: mdl-31053734

ABSTRACT

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.


Subject(s)
Actin Cytoskeleton/drug effects , Antineoplastic Agents/adverse effects , Dasatinib/adverse effects , Podocytes/pathology , Protein Kinase Inhibitors/adverse effects , Renal Insufficiency, Chronic/pathology , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Animals , Cell Line , Disease Models, Animal , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mice , Podocytes/drug effects , Podocytes/metabolism , Renal Insufficiency, Chronic/chemically induced , United States , United States Food and Drug Administration
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