Proplatelet formation deficit and megakaryocyte death contribute to thrombocytopenia in Myh9 knockout mice
Proplatelet formation deficit and megakaryocyte death contribute to thrombocytopenia in Myh9 knockout mice
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DOI：
10.1111/j.1538-7836.2010.04009.x
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发表时间：
2010-10-01
影响因子：
10.4
通讯作者：
Leon, C.
中科院分区：
文献类型：
--
作者：
Eckly, A.;Rinckel, J. -Y.;Leon, C.
背景：小鼠Myh9基因（Myh9 Delta）的失活或其在MYH9相关疾病中的突变导致巨血小板减少症。有趣的是，以前的研究表明，在体外分化的巨核细胞时，肌球蛋白不存在或抑制的前血小板形成的能力增加。研究方法：为了探索肌球蛋白缺乏引起的血小板减少症的起源，我们使用野生型（WT）和Myh9 Delta小鼠的骨髓外植体研究了前血小板的形成，其中巨核细胞在其天然环境中已经成熟。结果和讨论：在Myh9 Delta小鼠的巨核细胞中观察到前血小板的数量和复杂性急剧下降，而blebbistatin抑制肌球蛋白活性增加WT成熟巨核细胞的前血小板形成。此外，Myh9 δ巨核细胞具有比WT细胞更小的尺寸。这些数据表明，肌球蛋白缺乏对前血小板形成产生负面影响，可能是通过损害原位巨核细胞成熟，而肌球蛋白活性在前血小板形成的最后阶段被抑制。此外，Myh9 Delta骨髓的超微结构检查显示，与WT小鼠相比，表现出非凋亡性细胞死亡迹象的巨核细胞比例增加。结论：这些数据表明，Myh9 Delta小鼠中的血小板减少症是由巨核细胞大小发育缺陷、前血小板形成受损和细胞死亡增加引起的。
Background: Inactivation of the mouse Myh9 gene (Myh9 Delta) or its mutation in MYH9-related diseases leads to macrothrombocytopenia. Paradoxically, previous studies using in vitro differentiated megakaryocytes showed an increased capacity for proplatelet formation when myosin was absent or inhibited. Methods: To explore the origin of the thrombocytopenia induced by myosin deficiency, we studied proplatelet formation using bone marrow explants of wild-type (WT) and Myh9 Delta mouse where megakaryocytes have matured in their native environment. Results and discussion: A dramatic decrease in the number and complexity of proplatelets was observed in megakaryocytes from Myh9 Delta mice, while inhibition of myosin activity by blebbistatin increased proplatelet formation from WT mature megakaryocytes. Moreover, Myh9 Delta megakaryocytes had a smaller size than the WT cells. These data indicate that myosin deficiency acts negatively on proplatelet formation, probably by impairing in situ megakaryocyte maturation, while myosin activity is dispensable at the latest stage of proplatelet formation. In addition, ultrastructural examination of Myh9 Delta bone marrow revealed an increased proportion of megakaryocytes exhibiting signs of non-apoptotic cell death as compared with the WT mice. Conclusion: These data indicate that thrombocytopenia in Myh9 Delta mice results from defective development of megakaryocyte size, impaired proplatelet formation and increased cell death.