Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1
Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1
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DOI：
10.1182/blood-2001-12-0271
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发表时间：
2002-06-01
期刊：
影响因子：
20.3
通讯作者：
Sims, PJ
中科院分区：
文献类型：
--
作者：
Zhou, QS;Zhao, J;Sims, PJ
磷脂攀爬酶1（PLSCR 1）是一种内面质膜蛋白，被认为参与磷脂酰丝氨酸和其他磷脂的跨双层运动。除了其在质膜磷脂重组中的假定作用外，PLSCR 1是细胞内激酶的底物，这意味着其可能参与增殖、分化或凋亡的各种信号通路。由于PLSCR 1在多种血细胞中显著表达，我们评估了PLSCR 1敲除小鼠的血小板和红细胞中的PLSCR活性以及造血前体细胞的精氨酸依赖性生长。成年PLSCR 1（-/-）小鼠没有表现出明显的血液学或止血异常，这些动物的血细胞在刺激时通常将磷脂酰丝氨酸动员到细胞表面。尽管成年PLSCR 1（-/-）小鼠的血细胞计数正常，但相对于年龄匹配的野生型（WT），胎儿和新生动物的中性粒细胞计数均显著降低。此外，与WT相比，PLSCR 1（-/-）小鼠的造血前体细胞在干细胞因子和粒细胞集落刺激因子（GCSF）的刺激下表现出集落形成缺陷和向成熟粒细胞分化受损。相比之下，PLSCR 1（-/-）细胞表现出正常的集落形成刺激白细胞介素-3或粒细胞-巨噬细胞CSF，血小板生成素或促红细胞生成素的巨核细胞和红系祖细胞的扩增不受影响。还发现干细胞因子和G-CSF诱导WT细胞中PLSCR 1水平的显著增加。与体外试验一致，用G-CSF处理的PLSCR 1（-/-）小鼠显示在相同处理的WT小鼠中观察到的粒细胞增多少于50%。这些数据提供了PLSCR 1在功能上有助于尼古丁调节的细胞增殖和分化的直接证据，并表明它是正常骨髓生成所必需的。(C)2002年，美国血液学会。
Phospholipid scramblase 1 (PLSCR1) is an endofacial plasma membrane protein proposed to participate in transbilayer movement of phosphatidylserine and other phospholipids. In addition to its putative role in the reorganization of plasma membrane phospholipids, PLSCR1 is a substrate of intracellular kinases that imply its possible participation in diverse signaling pathways underlying proliferation, differentiation, or apoptosis. Because PLSCR1 is prominently expressed in a variety of blood cells, we evaluated PLSCR activity in platelets and erythrocytes, and cytokine-dependent growth of hematopoietic precursor cells, of PLSCR1 knock-out mice. Adult PLSCR1(-/-) mice showed no obvious hematologic or hemostatic abnormality, and blood cells from these animals normally mobilized phosphatidylserine to the cell surface upon stimulation. Whereas blood cell counts in adult PLSCR1(-/-) mice were normal, in both fetus and newborn animals neutrophil counts were significantly depressed relative to age-matched wild type (WT). Furthermore, when compared with WT, hematopoietic precursor cells from PLSCR1(-/-) mice showed defective colony formation and impaired differentiation to mature granulocytes as stimulated by stem cell factor and granulocyte colony-stimulating factor (GCSF). By contrast, PLSCR1(-/-) cells showed normal colony formation stimulated by interleukin-3 or granulocyte-macrophage CSF, and expansion of megakaryocytic and erythroid progenitors by thrombopoietin or erythropoietin was unaffected. Stem cell factor and G-CSF were also found to induce marked Increases In PLSCR1 levels In WT cells. Consistent with In vitro assays, PLSCR1(-/-) mice treated with G-CSF showed less than 50% of the granulocytosis observed In Identically treated WT mice. These data provide direct evidence that PLSCR1 functionally contributes to cytokine-regulated cell proliferation and differentiation and suggest It Is required for normal myelopoiesis. (C) 2002 by The American Society of Hematology.