The role of Piezo 1 in mechanosensing and mechanotransduction of migrating platelets

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Platelets are at the forefront of the mammalian immune response and patrol the vasculature for signs of injury and inflammation. When a vessel springs a leak, platelets instantaneously get activated and seal the lesion by forming a plug – a process termed hemostasis. While physiological hemostasis is essential for maintaining vascular integrity and vital to life, dysregulation of platelet activation causes detrimental thrombotic vascular occlusions. Pathological thrombosis is associated with inflammatory conditions such as atherosclerosis and deep vein thrombosis, but also occurs in systemic viral and bacterial infections. Recent studies have shown that platelets have the ability to migrate. Migrating platelets mechanical probe their environment and directionally migrate towards higher concentrations of the extracellular matrix. This guides platelets to sites of vascular injury and is essential for precise plugging of microlesions in inflamed blood vessels. However, the role of platelet migration reaches beyond hemostasis. Platelets migrate to scan their environment for pathogenic invaders and pile up bacteria to prevent their dissemination within the organism and to fuel the host immune response. Consequently, a mechanistic understanding of the molecular basis of platelet migration may offer the unique opportunity to develop novel therapeutic strategies in the treatment or prevention of thrombotic and infectious diseases. The mechanosensing and -transduction events that initiate and control platelet migration however remain unknown. Calcium signaling plays a crucial role in mechanotransduction of migrating cells and influx of extracellular calcium is essential for platelet migration. Platelets express a plethora of calcium channels in the plasma membrane including mechanosensitive calcium channels which are evolutionary conserved integral membrane proteins known to regulate cell migration. Piezo 1 is a member of a newly discovered family of mechanosensitive channels and, despite only recently being identified, it has been linked to several human pathologies. Piezo 1 is expressed in platelets and was shown to play a role in platelet activation. Based on our preliminary data we hypothesize that Piezo 1 activation plays a crucial role for mechanosening of migrating platelets. Our aims are to dissect (1) the mechanisms of Piezo 1-mediated mechanosensing in migrating platelets, (2) the molecular downstream targets of Piezo 1-mediated calcium influx in platelets, and (3) the role of Piezo 1 activation in mouse models of hemostasis, thrombosis and infection.