An endogenous vitamin K-dependent mechanism regulates cell proliferation in the brain subventricular stem cell niche.
An endogenous vitamin K-dependent mechanism regulates cell proliferation in the brain subventricular stem cell niche.
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DOI：
10.1002/stem.1045
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发表时间：
2012-04
期刊：
影响因子：
5.2
通讯作者：
Benzakour, Omar
中科院分区：
文献类型：
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作者：
Gely-Pernot, Aurore;Coronas, Valerie;Harnois, Thomas;Prestoz, Laetitia;Mandairon, Nathalie;Didier, Anne;Berjeaud, Jean Marc;Monvoisin, Arnaud;Bourmeyster, Nicolas;Garcia De Frutos, Pablo;Philippe, Michel;Benzakour, Omar
神经干细胞（NSC）存在于成年哺乳动物脑的脑室下区（SVZ）。支持SVZ干细胞和祖细胞增殖的内源性机制尚未完全阐明。维生素K依赖性蛋白（VKDPs）主要是分泌因子，最初被发现是血液凝固的主要调节因子。华法林（（S（−）-3-acetonylbenzyl）-4-hydroxycoumarin））是一种广泛使用的抗凝剂，是一种维生素K拮抗剂，可抑制功能性VKDP的产生。我们证明，抑制功能性VKDPs的生产，在体外，暴露于华法林的SVZ细胞培养物，或在体内，通过其脑室内注射给小鼠，导致SVZ细胞增殖的大幅增加。我们确定的抗凝因子，蛋白S和其结构同源Gas 6，作为两个只有VKDP产生的SVZ细胞和描述的表达和激活模式的Tyro 3，Axl和Mer酪氨酸激酶受体。无论是在体外和体内的功能丧失的研究，在Gas 6基因失效或内源性蛋白S中和，这两个VKDP在SVZ神经原性生态位的重要的新的调节作用提供了证据。具体来说，我们表明，虽然Gas 6的损失导致干细胞样细胞的数量减少，在嗅球神经发生，内源性蛋白S抑制SVZ细胞增殖。我们的研究为进一步研究维生素K，VKDP和抗凝剂在NSC生物学中在健康和疾病中的作用开辟了新的视角。干细胞2012; 30：719-731
Neural stem cells (NSC) persist in the adult mammalian brain, within the subventricular zone (SVZ). The endogenous mechanisms underpinning SVZ stem and progenitor cell proliferation are not fully elucidated. Vitamin K-dependent proteins (VKDPs) are mainly secreted factors that were initially discovered as major regulators of blood coagulation. Warfarin ((S(−)-3-acetonylbenzyl)-4-hydroxycoumarin)), a widespread anticoagulant, is a vitamin K antagonist that inhibits the production of functional VKDP. We demonstrate that the suppression of functional VKDPs production, in vitro, by exposure of SVZ cell cultures to warfarin or, in vivo, by its intracerebroventricular injection to mice, leads to a substantial increase in SVZ cell proliferation. We identify the anticoagulant factors, protein S and its structural homolog Gas6, as the two only VKDPs produced by SVZ cells and describe the expression and activation pattern of their Tyro3, Axl, and Mer tyrosine kinase receptors. Both in vitro and in vivo loss of function studies consisting in either Gas6 gene invalidation or in endogenous protein S neutralization, provided evidence for an important novel regulatory role of these two VKDPs in the SVZ neurogenic niche. Specifically, we show that while a loss of Gas6 leads to a reduction in the numbers of stem-like cells and in olfactory bulb neurogenesis, endogenous protein S inhibits SVZ cell proliferation. Our study opens up new perspectives for investigating further the role of vitamin K, VKDPs, and anticoagulants in NSC biology in health and disease. Stem Cells 2012; 30:719–731
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影响因子：
6.1
作者：
Kernie SG;Parent JM
通讯作者：
Parent JM
影响因子：
6.1
作者：
Baker, SA;Baker, KA;Hagg, T
通讯作者：
Hagg, T
DOI：
10.1073/pnas.0603512103
发表时间：
2006-08-29
影响因子：
11.1
作者：
Jin, Kunlin;Wang, Xiaomei;Greenberg, David A.
通讯作者：
Greenberg, David A.
DOI：
10.1073/pnas.0909333107
发表时间：
2010-01-19
影响因子：
11.1
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
通讯作者：
Lorens, James B.
DOI：
10.2174/157489006778777016
发表时间：
2006-11-01
期刊：
Recent patents on cardiovascular drug discovery
影响因子：
--
作者：
Desai, Sapan S;Massad, Malek G;Geha, Alexander S
通讯作者：
Geha, Alexander S