Abstract
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
Highlights
In the adult mammalian organism, tissue-specific stem cells replenish throughout life organs by replacing lost cells [1]
We identify the anticoagulant factors, protein S and its structural homolog Gas6, as the two only VKDPs produced by subventricular zone (SVZ) cells and describe the expression and activation pattern of their Tyro3, Axl, and Mer tyrosine kinase receptors
SVZ neural stem cells (NSCs) provide a continuous supply of neuroblasts that migrate toward the olfactory bulb, where they ensure turnover of interneurons, and give birth to glial cells that disperse in the white matter of diverse brain regions [2,3,4]
Summary
In the adult mammalian organism, tissue-specific stem cells replenish throughout life organs by replacing lost cells [1]. SVZ neural stem cells (NSCs) provide a continuous supply of neuroblasts that migrate toward the olfactory bulb, where they ensure turnover of interneurons, and give birth to glial cells that disperse in the white matter of diverse brain regions [2,3,4]. Brain injuries including neurodegenerative diseases or ischemia are believed to mobilize NSCs, providing thereby neuroblasts to injured brain areas that replace part of dying neurons [5,6,7,8]. Cues derived from NSC and from the surrounding cells of the stem cell niche as well as signals of remote brain areas regulate NSC proliferation and differentiation of their progenies [9,10,11]. Much attention has been devoted to identifying exogenous factors that promote neural stem and progenitor cell proliferation [9,10,11,12,13], little is known of the endogenous regulatory mechanisms, the inhibitory ones that may constitutively contribute to regulating cell proliferation within the SVZ stem cell niche or within other stem cell niches
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