Shear enhances thrombopoiesis and formation of microparticles that induce megakaryocytic differentiation of stem cells
Shear enhances thrombopoiesis and formation of microparticles that induce megakaryocytic differentiation of stem cells
复制标题
DOI：
10.1182/blood-2014-01-547927
复制
发表时间：
2014-09-25
期刊：
影响因子：
20.3
通讯作者：
Papoutsakis, Eleftherios T.
中科院分区：
文献类型：
--
作者：
Jiang, Jinlin;Woulfe, Donna S.;Papoutsakis, Eleftherios T.
在体内可视化的血小板生成表明，剪切流在血小板生物合成的重要作用。在体外，剪切应力被证明可以加速成熟巨核细胞（Mks）的前血小板形成。然而，MK生物学和血小板生物发生的生物力学力的作用仍然在很大程度上未被探索。在这项研究中，我们研究了剪切应力对Mk成熟和血小板样颗粒（PLPs），前/preplatelets（PPT）和Mk微粒（MkMPs）形成的影响，此外，我们还探讨了MkMPs的生理作用。我们发现，剪切加速DNA合成的未成熟的MKS在曝光时间和剪切应力水平依赖的方式。磷脂酰丝氨酸暴露和caspase-3激活增强剪切应力。暴露于生理剪切显著增加PLPs/PPT和MkMP的产生，分别高达10.8和47倍。Caspase-3抑制减少剪切诱导的PLP/PPT和MkMP形成。剪切流下产生的PLPs显示出改善的功能，如通过CD 62 P暴露和纤维蛋白原结合评估的。值得注意的是，MkMPs与造血干细胞和祖细胞的共培养促进造血干细胞和祖细胞分化为成熟的Mks，合成α-和致密颗粒，并在没有外源性血小板生成素的情况下形成PPT，从而鉴定了MkMPs的新的和未探索的潜在生理作用。
In vivo visualization of thrombopoiesis suggests an important role for shear flow in platelet biogenesis. In vitro, shear stress was shown to accelerate proplatelet formation from mature megakaryocytes (Mks). Yet, the role of biomechanical forces on Mk biology and platelet biogenesis remains largely unexplored. In this study, we investigated the impact of shear stress on Mk maturation and formation of platelet-like particles (PLPs), pro/preplatelets (PPTs), and Mk microparticles (MkMPs), and furthermore, we explored a physiological role for MkMPs. We found that shear accelerated DNA synthesis of immature Mks in an exposure time-and shear stress level-dependent manner. Both phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. Exposure to physiological shear dramatically increased generation of PLPs/PPTs and MkMPs by upto 10.8 and 47-fold, respectively. Caspase-3 inhibition reduced shear-induced PLP/PPT and MkMP formation. PLPs generated under shear flow displayed improved functionality as assessed by CD62P exposure and fibrinogen binding. Significantly, coculture of MkMPs with hematopoietic stem and progenitor cells promoted hematopoietic stem and progenitor cell differentiation to mature Mks synthesizing alpha-and dense-granules, and forming PPTs without exogenous thrombopoietin, thus identifying a novel and unexplored potential physiological role for MkMPs.