巨核细胞
菲拉明
细胞生物学
生物发生
生物
血小板
萌芽
化学
造血
遗传学
免疫学
细胞骨架
基因
细胞
干细胞
作者
Marc L Ellis,Antoine F Terreaux,Imala Alwis,Rhyll Smythe,José Perdomo,Anita Eckly,Susan L. Cranmer,Freda Passam,Jessica MacLean,Simone M. Schoenwaelder,Zaverio M. Ruggeri,François Lanza,Samir Taoudi,Yanbin Yuan,Shaun P. Jackson
出处
期刊:Blood
[American Society of Hematology]
日期:2024-01-25
卷期号:143 (4): 342-356
被引量:1
标识
DOI:10.1182/blood.2023021292
摘要
Abstract Glycoprotein Ibα (GPIbα) is expressed on the surface of platelets and megakaryocytes (MKs) and anchored to the membrane skeleton by filamin A (flnA). Although GPIb and flnA have fundamental roles in platelet biogenesis, the nature of this interaction in megakaryocyte biology remains ill-defined. We generated a mouse model expressing either human wild-type (WT) GPIbα (hGPIbαWT) or a flnA-binding mutant (hGPIbαFW) and lacking endogenous mouse GPIbα. Mice expressing the mutant GPIbα transgene exhibited macrothrombocytopenia with preserved GPIb surface expression. Platelet clearance was normal and differentiation of MKs to proplatelets was unimpaired in hGPIbαFW mice. The most striking abnormalities in hGPIbαFW MKs were the defective formation of the demarcation membrane system (DMS) and the redistribution of flnA from the cytoplasm to the peripheral margin of MKs. These abnormalities led to disorganized internal MK membranes and the generation of enlarged megakaryocyte membrane buds. The defective flnA-GPIbα interaction also resulted in misdirected release of buds away from the vasculature into bone marrow interstitium. Restoring the linkage between flnA and GPIbα corrected the flnA redistribution within MKs and DMS ultrastructural defects as well as restored normal bud size and release into sinusoids. These studies define a new mechanism of macrothrombocytopenia resulting from dysregulated MK budding. The link between flnA and GPIbα is not essential for the MK budding process, however, it plays a major role in regulating the structure of the DMS, bud morphogenesis, and the localized release of buds into the circulation.
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