Biology subjects

destaing, o.

Publications and source records attributed to destaing, o..

4 recordsLinked to original sources

bioRxiv2026

Endothelial gain of PIEZO/TRPV mechanosensors drives cavernous malformations

Vascular disease often begins as a failure to read mechanical force. Cerebral cavernous malformations (CCMs) are leaky, brain-invading capillary clusters that cause stroke and seizures and arise from endothelial loss of the CCM complex. They form exclusively in low-flow vessels but existing models cannot explain this selectivity. We previously established that CCM-mutant endothelium inverts its adhesive balance, weakening cell-cell junctions while building matrix-degrading adhesions. The mechanosensors imposing this switch are unknown. Here we show that the mechanosensitive Ca2+ channels PIEZO1, TRPV2 and TRPV4 are overexpressed in the endothelium of CCM lesions in a 42-patient cohort, and that lesion volume scales with their expression level. Mechanistically, PIEZO1 partners with TRPV4 to destabilise cell-cell junctions and with TRPV2 to reinforce cell-matrix adhesions; silencing TRPV4 restores junctional integrity and abolishes KLF4 induction, whereas silencing TRPV2 or inhibition with tranilast abolishes matrix degradation and invasion. In vivo, trpv4 knockdown or inhibition with GSK2798745 restores atrioventricular canal morphogenesis in ccm2-mutant zebrafish. Gain of mechanosensory channel function is thus a causal step in CCM pathogenesis, upstream of the KLF program. Combined therapeutic targeting of TRPV2 and TRPV4 with inhibitors validated in humans offers a route to therapy.

cell biology↗

bioRxiv2025

Optogenetic SH3 nanoclustering of SRC and HCK uncovers the functional specificity of these redundant kinases in macrophages.

Understanding redundancy among Src Family Kinases (SFKs) challenges how cells achieve signaling specificity using closely related enzymes, and paves the way to revisit a basic property of any cell signaling network. Optogenetic control of the adaptor properties of the most redundant SFK members, SRC and HCK, was used to examine their potential specificity in macrophages. Uncoupling their kinase and adaptor functions uncovers an unique mechanism driven by oligomerized- and SH3-dependent specific binding that enables inducing distinct signaling outputs for each kinase. OptoSRC and optoHCK probes revealed that SRC and HCK can trigger specific cellular responses, despite only supposed overlapping functions. The specificity of optoHCK even unveils a novel role in activating polarized clathrin hotspots essential for directional migration. Redundancy could be rebuilt within optoHCK through stepwise optogenetic reconstruction of adaptor modules revealing the essential role of both membrane anchoring and SH2-domain. This deconstructive approach of SFK activation elucidated the molecular basis of their shared and unique signaling activities and supports a model of cooperative functional entanglement between SFK members, rather than simple redundancy.

cell biology↗

bioRxiv2024

Megakaryocytes build a cage of extracellular matrix that controls their maturation and anchoring to the vascular niche

Megakaryocytes, the progenitor cells of blood platelets, play a crucial role in hemostasis by residing in the bone marrow and ensuring continuous platelet production. Unlike other hematopoietic cells, megakaryocytes do not enter the blood circulation intact. They remain anchored within the bone marrow while extending cytoplasmic protrusions called proplatelets through the sinusoidal endothelial barrier. These proplatelets subsequently fragment into functional platelets. This unique process of intravasation facilitates efficient platelet production while maintaining the megakaryocyte cell body within the bone marrow niche, thus preventing potential thrombotic complications. How the extracellular matrix (ECM) influences the delicate balance between megakaryocyte retention and proplatelet extension remains largely unknown. Here, we investigate the spatial organization and functional role of ECM components in the megakaryocyte vascular niche. Our findings reveal that laminin and collagen IV form three-dimensional (3D) ECM cages encompassing megakaryocytes and anchor them to the sinusoidal basement membrane. Gene deletion shows the existence of laminin 4 in the ECM cage that is necessary to maintain megakaryocyte-sinusoid interactions. Notably, megakaryocytes actively contribute to the ECM cage assembly; {beta}1/{beta}3 integrin knockout weakens these structures, increasing intravasation and entire megakaryocyte entry into circulation. The retention of megakaryocytes by these 3D ECM cages depends on dynamic remodeling processes. Inhibition of ECM proteolysis results in denser cage formation, increasing the frequence of immature megakaryocytes with impaired demarcation membrane system (DMS) development. Thus, the ECM cage represents a novel concept of an active and dynamic 3D microenvironment that is continuously remodeled and essential for maintaining megakaryocyte perivascular positioning. This specific microarchitecture guides megakaryocyte maturation and intravasation, underscoring the critical role of ECM microarchitecture and dynamics in megakaryocyte function. Key PointsO_LIMegakaryocytes form a three-dimensional (3D) cage composed of laminin and collagen IV connected to the basement membrane surrounding them. This microarchitecture stabilizes megakaryocytes within their vascular niche. C_LIO_LI{beta}1/{beta}3 integrins and MMP are key ECM cage regulators that assist megakaryocyte maturation and intravasation at the bone marrow-blood interface. C_LI

physiology↗

bioRxiv2021

CCM2 deficient endothelial cells undergo a mechano-dependent reprogramming into senescence associated secretory phenotype used to recruit endothelial and immune cells.

Cerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM diseases is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells enter into senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions. By this, we identify CCM1/2 and ROCKs as parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of aging by cellular mechanics. This discovery reconciles the dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent endothelial fate that links perturbed mechanics to microenvironment remodelling and long-range activation of endothelial and immune cells.

cell biology↗