Caspase activation is involved in early megakaryocyte differentiation but not in platelet production from megakaryocytes
Caspase activation is involved in early megakaryocyte differentiation but not in platelet production from megakaryocytes
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DOI：
10.1038/leu.2009.7
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发表时间：
2009-06-01
期刊：
影响因子：
11.4
通讯作者：
Kojima, H.
中科院分区：
文献类型：
--
作者：
Kozuma, Y.;Yuki, S.;Kojima, H.
为了阐明半胱天冬酶的激活是否参与巨核细胞的形成，我们的特点vav-bcl-2转基因（Tg）小鼠，其中Bcl-2在造血细胞中过表达的巨核细胞（MK）。为了排除Tg小鼠中脾肿大对巨核细胞生成的影响，进行脾切除术。脾切除术后，外周血中的基础血小板计数Tg和野生型（WT）小鼠之间没有显着差异。然而，当实验性血小板减少症诱导注射5-氟尿嘧啶到脾切除小鼠，血小板计数在恢复阶段的冲在Tg小鼠几乎没有观察到。在恢复期MK倍性的分析表明，小于16 N倍性的MK显着减少，在Tg小鼠，这表明MK供应从祖细胞受损。支持这一点的是，在Tg小鼠中，CD 34-/c-kit+/Sca-1+/谱系干细胞分化为MK显著受阻，而巨核细胞-红系祖细胞（MEP）正常分化为MK。提示在MEP期之前，Tg小鼠向MK的分化受损。此外，在存在半胱天冬酶抑制剂的情况下，WT细胞中MK集落形成受到剂量依赖性抑制。相反，Bcl-2过表达的MK显示出正常的体外血小板生成能力。因此，我们认为，半胱天冬酶的激活参与祖细胞分化成巨核细胞谱系，但不是在血小板的生产。Leukemia（2009）23，1080-1086; doi：10.1038/leu.2009.7; 2009年2月12日在线发表
To elucidate whether caspase activation is involved in megakaryopoiesis, we characterized megakaryocytes (MKs) in vav-bcl-2 transgenic (Tg) mice, in which Bcl-2 is overexpressed in hematopoietic cells. To exclude the effect of splenomegaly in Tg mice on megakaryopoiesis, splenectomy was performed. After splenectomy, basal platelet counts in peripheral blood were not significantly different between Tg and wild-type (WT) mice. However, when experimental thrombocytopenia was induced by injecting 5-fluorouracil into splenectomized mice, overshoot of platelet counts during the recovery phase was hardly observed in Tg mice. Analyses of MK ploidy during the recovery phase showed that MKs less than 16N ploidy were significantly decreased in Tg mice, suggesting that MK supply from progenitors is impaired. Supporting this, differentiation of CD34-/c-kit+/Sca-1+/Lineage- stem cells into MKs was significantly hampered in Tg mice, whereas megakaryocyte-erythroid progenitors (MEPs) normally differentiated into MKs. It suggests that differentiation into MKs is impaired in Tg mice before the stage of MEP. Furthermore, MK colony formation in WT cells was dose-dependently inhibited in the presence of a caspase inhibitor. Contrary, Bcl-2-overexpressing MKs showed normal ability for in vitro platelet production. We thus believe that caspase activation is involved in the differentiation of progenitors into megakaryocytic lineage but not in platelet production. Leukemia (2009) 23, 1080-1086; doi: 10.1038/leu.2009.7; published online 12 February 2009