Integrin β3 dysregulation impairs megakaryopoiesis and microparticle production via disrupting Rho-associated protein kinase-dependent cytoskeletal dynamics.
Wen Wang, Juping Zhai, Yao Wang, Xinyu Li, Jianfeng Yang, Zhen Weng, Yunxiao Zhao, Qingyu Wu, Bin Zuo, Yang He
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引用次数: 0
Abstract
Background: Megakaryocyte (MK) fragmentation into proplatelets (PPTs) and microparticles (megakaryocyte-derived microparticles [MKMPs]) is well established, yet the mechanisms underlying MKMP generation remain unclear.
Objectives: This study aimed to investigate the role of integrin β3 and cytoskeletal dynamics during megakaryopoiesis and explore potential therapeutic targets for thrombocytopenia.
Methods: Proplatelet formation and MKMP release were evaluated both in vivo and in vitro under integrin β3 receptor-impaired environment. The integrin activation and RhoA-associated kinase triggered signaling were analyzed.
Results: In human MK cultures, we demonstrated that the anti-β3 antibody SZ21 hyperactivated RhoA‒Rho-associated protein kinase (ROCK) signaling, stabilizing F-actin polymerization via LIM kinase/myosin light chain 2 phosphorylation and impairing both PPT and MKMP release. MKMP release depends on actin depolymerization, whereas PPT formation requires microtubule assembly and actomyosin contraction, revealing differential cytoskeletal regulation among megakaryocytic byproducts. Pharmacologic ROCK inhibition with Y27632 rescued these defects in vitro and accelerated platelet recovery in thrombocytopenic mice without compromising hemostasis.
Conclusions: Our study reveals a novel dysregulation of the integrin β3-ROCK axis in immune-mediated MK dysfunction and suggests that targeting ROCK signaling or cytoskeletal dynamics may represent promising therapeutic strategies for thrombocytopenia and other disorders affecting platelet production.
期刊介绍：
The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community.
Types of Publications:
The journal publishes a variety of content, including:
Original research reports
State-of-the-art reviews
Brief reports
Case reports
Invited commentaries on publications in the Journal
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Scope of Contributions:
Editors invite contributions from both fundamental and clinical domains. These include:
Basic manuscripts on blood coagulation and fibrinolysis
Studies on proteins and reactions related to thrombosis and haemostasis
Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms
Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases
Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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