Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice
Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice
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DOI：
10.1172/jci69210
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Nieswandt, Bernhard
中科院分区：
文献类型：
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作者：
Deppermann, Carsten;Cherpokova, Deya;Nieswandt, Bernhard
血小板是来源于骨髓巨核细胞（mk）的富含核细胞器的细胞片段，可保护血管的完整性。主要的血小板细胞器α -颗粒释放参与血栓形成和止血的蛋白质。储存在α -颗粒中的蛋白质也被认为在炎症和伤口愈合中发挥作用，但它们在体内的功能意义尚不清楚。NBEAL2突变与灰色血小板综合征（GPS）有关，灰色血小板综合征是一种罕见的出血性疾病，以大量血小板减少为特征，血小板缺乏α颗粒。在这里，我们发现nbeal2基因敲除小鼠表现出人类GPS的特征，mk中的α颗粒生物发生缺陷，并且它们在血小板中缺失。Nbeal2缺乏不影响体外MK分化和血小板形成，也不影响体内血小板寿命。缺乏nbeal2的血小板在体外表现出粘附、聚集和凝血活性受损，这导致动脉血栓形成缺陷和局灶性脑缺血后血栓炎性脑梗死的保护。在切除性皮肤伤口修复模型中，nbeal2缺陷小鼠由于缺乏α颗粒分泌而导致肌成纤维细胞分化严重减少，表现出功能性肉芽组织发育受损。这项研究表明，血小板α颗粒成分不仅对止血至关重要，而且对血栓形成、急性血栓炎性疾病状态和损伤后的组织重建也至关重要。
Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, alpha-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in alpha-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking alpha-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective alpha-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of alpha-granule secretion. This study demonstrates that platelet alpha-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.