Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production
Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production
复制标题
DOI：
10.1182/blood-2010-09-305540
复制
发表时间：
2011-04-28
期刊：
影响因子：
20.3
通讯作者：
Atweh, George F.
中科院分区：
文献类型：
--
作者：
Iancu-Rubin, Camelia;Gajzer, David;Atweh, George F.
巨核细胞（MK）成熟的最后阶段涉及一系列步骤，包括多倍化和前血小板形成。尽管这些过程高度依赖于微管（MT）细胞骨架的动态变化，但负责调节MK中MT的机制仍不清楚。Stathmin是一种高度保守的MT调节蛋白，已被认为在人白血病细胞系的MK分化中发挥作用。然而，以前的研究定义这种关系已经得出了相互矛盾的结论。在这项研究中，我们解决了这一争议，并调查了stathmin在原代人MK中的作用。为了探讨stathmin下调在巨核细胞生成过程中的重要性，我们使用慢病毒介导的基因递送系统来防止原发性MK中stathmin的生理性下调。我们证明，持续表达的组成型活性stathmin延迟细胞质成熟（即，糖蛋白GPIb和血小板因子4的表达），并降低MK的能力，以实现高水平的倍性。此外，血小板生产受损的MK中，其中stathmin表达的下调被阻止。这些研究表明，抑制stathmin是生物学上的重要MK成熟和血小板的生产，并支持MT调节的重要性，在血小板生成的最后阶段。（血。2011; 117（17）：4580-4589）
The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relation-ship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis. (Blood. 2011; 117(17):4580-4589)