Regulation of Platelet Integrin Mechanobiology by Talin

By Liao, Jiexi

Georgia Institute of Technology

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Abstract

Advisors: Cheng Zhu, Shaun P Jackson, Brian G Petrich, Manu O Platt, Shuichi Takayama

Platelets are exquisitely reactive to mechanical forces in disturbed blood flow caused by vessel branching, stenosis, and interventional medical devices, leading to life-threatening clots comprised of platelet aggregates. How forces drive platelet aggregation on the molecular level is incompletely understood. Integrins, particularly the platelet-specific aIIbb3 (GPIIbIIIa), mediate the gradient shear-induced platelet aggregation not in their well-known fully activated form but an intermediate state. This intermediate state can be induced by merely mechano-signaling of GPIba, the receptor that initiates platelet rolling on endothelium. Since integrins require the cytoplasmic adaptor molecule, talin, for activation and cytoskeletal linkage, elucidating talin's role is critical to understand this process. Using stenosis-modeling microfluidics and mouse models that perturb specific interactions in the Rap-1-talin-integrin axis, we first demonstrated that talin indeed regulates platelet aggregation in disturbed flow and proposed the mechanism that aggregate buildup is achieved by membrane-recruited talin providing cytoskeletal linkage to the integrins. Our results also suggested that GPIba-induced GPIIbIIIa maturation to the intermediate state requires normal talin-integrin binding. To gain mechanistic insights on the molecular level, we used single-cell force spectroscopy to characterize the two-dimensional kinetics of integrin-ligand binding with talin perturbations in the presence and absence of force. We found that talin, a mechanosensor itself, is particularly important for force-mediated integrin binding without prior inside-out activation. The formation of catch bond (force prolonged bond lifetime) between the fibrinogen ligand and b3 integrin may be crucial for the "biomechanical" platelet aggregation in disturbed flow. Lastly, we extended the platelet mechanobiology study to investigate a disease known to dysregulate platelets: diabetes. We focused on type I diabetes to reduce metabolic confounding factors. Using the stenosis microfluidics to screen patients' blood, we preliminarily concluded that diabetes could amplify platelet aggregation by promoting more integrins to the intermediate state, but many other factors including racial heritage could cause large variance in patient samples' responses. Overall, we identified talin's critical role in gradient shear-induced platelet aggregation. The biophysics studies offered a clearer understanding of how integrins finely tune their kinetics in response to mechanical cues. Our results showed the anti-thrombotic potential of specific talin and Rap1 blockade and could inform rational design of novel therapeutics that address the mechanosensitivity of integrins.

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Researchers should cite this work as follows:

  • Liao, Jiexi (2021), "Regulation of Platelet Integrin Mechanobiology by Talin," https://matin.gatech.edu/resources/4225.

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