Subventricular Zone Neurogenic Niche Research Articles

Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective.

Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.

Vitamin C Deficiency Reduces Neurogenesis and Proliferation in the SVZ and Lateral Ventricle Extensions of the Young Guinea Pig Brain.

Although scurvy, the severe form of vitamin C deficiency, has been almost eradicated, the prevalence of subclinical vitamin C deficiency is much higher than previously estimated and its impact on human health might not be fully understood. Vitamin C is an essential molecule, especially in the central nervous system where it performs numerous, varied and critical functions, including modulation of neurogenesis and neuronal differentiation. Although it was originally considered to occur only in the embryonic brain, it is now widely accepted that neurogenesis also takes place in the adult brain. The subventricular zone (SVZ) is the neurogenic niche where the largest number of new neurons are born; however, the effect of vitamin C deficiency on neurogenesis in this key region of the adult brain is unknown. Therefore, through BrdU labeling, immunohistochemistry, confocal microscopy and transmission electron microscopy, we analyzed the proliferation and cellular composition of the SVZ and the lateral ventricle (LVE) of adult guinea pigs exposed to a vitamin-C-deficient diet for 14 and 21 days. We found that neuroblasts in the SVZ and LVE were progressively and significantly decreased as the days under vitamin C deficiency elapsed. The neuroblasts in the SVZ and LVE decreased by about 50% in animals with 21 days of deficiency; this was correlated with a reduction in BrdU positive cells in the SVZ and LVE. In addition, the reduction in neuroblasts was not restricted to a particular rostro–caudal area, but was observed throughout the LVE. We also found that vitamin C deficiency altered cellular morphology at the ultrastructural level, especially the cellular and nuclear morphology of ependymal cells of the LVE. Therefore, vitamin C is essential for the maintenance of the SVZ cell populations required for normal activity of the SVZ neurogenic niche in the adult guinea pig brain. Based on our results from the guinea pig brain, we postulate that vitamin C deficiency could also affect neurogenesis in the human brain.

Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice.

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.

Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches.

Fractones, specialized extracellular matrix structures found in the subventricular zone (SVZ) neurogenic niche, can capture growth factors, such as basic fibroblast growth factor, from the extracellular milieu through a heparin-binding mechanism for neural stem cell (NSC) presentation, which promotes neurogenesis. During aging, a decline in neurogenesis correlates with a change in the composition of heparan sulfate (HS) within fractones. In this study, we used antibodies that recognize specific short oligosaccharides with varying sulfation to evaluate the HS composition in fractones in young and aged brains. To further understand the conditions that regulate 6-O sulfation levels and its impact on neurogenesis, we used endosulfatase Sulf1 and Sulf2 double knockout (DKO) mice. Fractones in the SVZ of Sulf1/2 DKO mice showed immunoreactivity for the HS epitope, suggesting higher 6-O sulfation. While neurogenesis declined in the aged SVZ of both wild-type and Sulf1/2 DKO mice, we observed a larger number of neuroblasts in the young and aged SVZ of Sulf1/2 DKO mice. Together, these results show that the removal of 6-O-sulfation in fractones HS by endosulfatases inhibits neurogenesis in the SVZ. Our findings advance the current understanding regarding the extracellular environment that is best suited for NSCs to thrive, which is critical for the design of future stem cell therapies.

HPG-Dependent Peri-Pubertal Regulation of Adult Neurogenesis in Mice.

Adult neurogenesis, a striking form of neural plasticity, is involved in the modulation of social stimuli driving reproduction. Previous studies on adult neurogenesis have shown that this process is significantly modulated around puberty in female mice. Puberty is a critical developmental period triggered by increased secretion of the gonadotropin releasing hormone (GnRH), which controls the activity of the hypothalamic-pituitary-gonadal axis (HPG). Secretion of HPG-axis factors at puberty participates to the refinement of neural circuits that govern reproduction. Here, by exploiting a transgenic GnRH deficient mouse model, that progressively loses GnRH expression during postnatal development (GnRH::Cre;DicerloxP/loxP mice), we found that a postnatally-acquired dysfunction in the GnRH system affects adult neurogenesis selectively in the subventricular-zone neurogenic niche in a sexually dimorphic way. Moreover, by examining adult females ovariectomized before the onset of puberty, we provide important evidence that, among the HPG-axis secreting factors, the circulating levels of gonadal hormones during pre-/peri-pubertal life contribute to set-up the proper adult subventricular zone-olfactory bulb neurogenic system.

CD8+ T cells are present at low levels in the white matter with physiological and pathological aging.

The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8+ cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3+, CD4+ and CD8+) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3+ and CD8+ cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.

Adaptive neurogenesis in the cerebral cortex and contralateral subventricular zone induced by unilateral cortical devascularization: Possible modulation by dopamine neurotransmission.

Understanding endogenous neurogenesis and neuronal replacement to mature circuits is a topic of discussion as a therapeutic alternative under acute and chronic neurodegenerative disorders. Adaptive neurogenic response may result as a result of ischemia which could support long-term recovery of behavioral functions. Endogenous sources of neural progenitors may be stimulated by changes in blood flow or neuromodulation. Using a mouse model of unilateral cortical devascularization, we have observed reactive neurogenesis in the perilesional cortex and subventricular zone neurogenic niche. C57BL/6L 4weeks old male mice were craneotomized at 1mm caudal from frontal suture and 1mm lateral from midline to generate a window of 3mm side. Brain injury was produced by removal of the meninges and superficial vasculature of dorsal parietal cortex. BrdU agent (50mg/kg, ip) was injected to lesioned and sham animals, during days 0 and 1 after surgery. Sagittal sections were analyzed at 1, 4, 7, and 10days post-injury. A time-dependent increase in BrdU+ cells in the perilesional parietal cortex was accompanied by augmented BrdU+ cells in the sub ventricular and rostral migratory stream of ipsilateral and contralateral hemispheres. Neural progenitors and neuroblasts proliferated in the lesioned and non-lesioned subventricular zone and rostral migratory stream on day 4 after injury. Augmented contralateral neurogenesis was associated with an increase in vesicular monoamine transporter 2 protein in the striosomal sub ventricular neurogenic niche of non-lesioned hemisphere.

Interactions Between Neural Progenitor Cells and Microglia in the Subventricular Zone: Physiological Implications in the Neurogenic Niche and After Implantation in the Injured Brain.

The adult subventricular zone (SVZ) of the mammalian brain contains neural progenitor cells (NPCs) that continuously produce neuroblasts throughout life. These neuroblasts migrate towards the olfactory bulb where they differentiate into local interneurons. The neurogenic niche of the SVZ includes, in addition to NPCs and neuroblasts, astrocytes, ependymal cells, blood vessels and the molecules released by these cell types. In the last few years, microglial cells have also been included as a key component of the SVZ neurogenic niche. Microglia in the SVZ display unique phenotypic features, and are more densely populated and activated than in non-neurogenic regions. In this article we will review literature reporting microglia-NPC interactions in the SVZ and the role of this bilateral communication in microglial function and in NPC biology. This interaction can take place through the release of soluble factors, extracellular vesicles or gap junctional communication. In addition, as NPCs are used for cell replacement therapies, they can establish therapeutically relevant crosstalks with host microglia which will also be summarized throughout the article.

Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis.

Multiple sclerosis (MS) frequently starts near the lateral ventricles, which are lined by subventricular zone (SVZ) progenitor cells that can migrate to lesions and contribute to repair. Because MS-induced inflammation may decrease SVZ proliferation and thus limit repair, we studied the role of galectin-3 (Gal-3), a proinflammatory protein. Gal-3 expression was increased in periventricular regions of human MS in post-mortem brain samples and was also upregulated in periventricular regions in a murine MS model, Theiler's murine encephalomyelitis virus (TMEV) infection. Whereas TMEV increased SVZ chemokine (CCL2, CCL5, CCL, and CXCL10) expression in wild type (WT) mice, this was inhibited in Gal-3(-/-) mice. Though numerous CD45+ immune cells entered the SVZ of WT mice after TMEV infection, their numbers were significantly diminished in Gal-3(-/-) mice. TMEV also reduced neuroblast and proliferative SVZ cell numbers in WT mice but this was restored in Gal-3(-/-) mice and was correlated with increased numbers of doublecortin+ neuroblasts in the corpus callosum. In summary, our data showed that loss of Gal-3 blocked chemokine increases after TMEV, reduced immune cell migration into the SVZ, reestablished SVZ proliferation and increased the number of progenitors in the corpus callosum. These results suggest Gal-3 plays a central role in modulating the SVZ neurogenic niche's response to this model of MS.

Fractone aging in the subventricular zone of the lateral ventricle

In adulthood, the subventricular zone (SVZ) is one of the restricted places where neurogenesis persists. In this neurogenic niche, specialized extracellular matrix (ECM) structures termed fractones contact neural stem cells and their immediate progeny. Fractones are composed of ubiquitous ECM components including heparan sulfate proteoglycans such as perlecan and agrin. We have previously shown that fractones can capture growth factors and promote growth factor activity through a heparin binding mechanism in order to regulate neurogenesis. With aging, neurogenesis is known to decrease. However, the effect of aging on fractones structure and composition remains unknown. Here, we report that, while fractone number decreased, fractone size dramatically increased with aging. Despite the changes in fractones morphology, niche cells expressing glial fibrillary acidic protein kept direct contact with fractones. Furthermore, we have observed that heparan sulfate chains contained in fractones were modified with aging. However, FGF-2 was still captured by fractones via heparan sulfates. Together, our results suggest that the changes observed in fractones structure and composition are critically related to aging of the SVZ neurogenic niche.

Evidence for a subventricular zone neural stem cell phagocytic activity stimulated by the vitamin K-dependent factor protein S.

Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 µm latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell-derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology.

NFIX Regulates Proliferation and Migration Within the Murine SVZ Neurogenic Niche.

Transcription factors of the nuclear factor one (NFI) family play a pivotal role in the development of the nervous system. One member, NFIX, regulates the development of the neocortex, hippocampus, and cerebellum. Postnatal Nfix(-/-) mice also display abnormalities within the subventricular zone (SVZ) lining the lateral ventricles, a region of the brain comprising a neurogenic niche that provides ongoing neurogenesis throughout life. Specifically, Nfix(-/-) mice exhibit more PAX6-expressing progenitor cells within the SVZ. However, the mechanism underlying the development of this phenotype remains undefined. Here, we reveal that NFIX contributes to multiple facets of SVZ development. Postnatal Nfix(-/-) mice exhibit increased levels of proliferation within the SVZ, both in vivo and in vitro as assessed by a neurosphere assay. Furthermore, we show that the migration of SVZ-derived neuroblasts to the olfactory bulb is impaired, and that the olfactory bulbs of postnatal Nfix(-/-) mice are smaller. We also demonstrate that gliogenesis within the rostral migratory stream is delayed in the absence of Nfix, and reveal that Gdnf (glial-derived neurotrophic factor), a known attractant for SVZ-derived neuroblasts, is a target for transcriptional activation by NFIX. Collectively, these findings suggest that NFIX regulates both proliferation and migration during the development of the SVZ neurogenic niche.

Gli3 Repressor Controls Cell Fates and Cell Adhesion for Proper Establishment of Neurogenic Niche

Neural stem cells (NSCs) in the subventricular zone (SVZ) rely on environmental signals provided by the neurogenic niche for their proper function. However, little is known about the initial steps of niche establishment, as embryonic radial glia transition to postnatal NSCs. Here, we identify Gli3 repressor (Gli3R), a component of the Sonic hedgehog (Shh) pathway, as a critical factor controlling both cell-type specification and structural organization of the developing SVZ. We demonstrate that Gli3R expressed in radial glia temporally regulates gp130/STAT3 signaling at the transcriptional level to suppress glial characteristics in differentiating ependymal cells. In addition, Gli3R maintains the proper level of Numb in ependymal cells to allow localization of cell adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-cadherin. Thus, our findings reveal a role for Gli3R as a mediator of niche establishment and provide insights into the conditions required for proper SVZ neurogenic niche formation.

Identification of distinct ChAT⁺ neurons and activity-dependent control of postnatal SVZ neurogenesis.

Postnatal/adult SVZ neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular/niche-driven cues. Although behavioral paradigms and disease states have suggested possibilities for higher-level inputs, it is currently unknown if neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We have identified a previously undescribed population of ChAT+ neurons residing within the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts, and released acetylcholine locally in activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo showed that they are necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with FGF receptor activation to increase neuroblast production. These results uncovered an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control, and possibilities for modulating neuroregenerative capacities in health and disease.

Epidermal Growth Factor Treatment of the Adult Brain Subventricular Zone Leads to Focal Microglia/Macrophage Accumulation and Angiogenesis

SummaryOne of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

Extensive regenerative plasticity among adult NG2-glia populations is exclusively based on self-renewal

NG2-glia are known to proliferate in the adult brain, however the extent of their mitotic and regenerative capacity and particularly their adult origin is uncertain. By employing a paradigm of mitotic blockade in conjunction with genetic fate tracing we demonstrate that intracerebroventricular mitotic blocker infusion leads to wide-spread and complete ablation of NG2-glial cells in the hypothalamus and other periventricular brain regions. However, despite the extensive glia loss, parenchymal NG2-glia coverage is fully restored to pretreatment levels within two weeks. We further reveal that in response to mitotic blocker treatment, NG2-glia bordering the ablated territories start to express the stem cell marker nestin, divide and migrate to replace the lost cells. Importantly, the migration front of repopulating NG2-glia invariably proceeds from the distal parenchyma towards the ventricles, ruling out contributions of the subventricular zone neurogenic niche or the corresponding area of the third ventricle as source of new NG2-glia. NG2-CreER-based fate tracing further substantiates that NG2-glia which have been spared from mitotic blockade are the sole source of regenerating NG2-glia. Collectively, our data reveals that all adult NG2-glia retain the ability to divide and that they are capable of fully restoring parenchymal NG2-glia coverage after wide-spread NG2 cell loss, indicating complete self-sufficiency in maintaining NG2-glia population levels in the adult brain.

Dynamic Activity of miR-125b and miR-93 during Murine Neural Stem Cell Differentiation In Vitro and in the Subventricular Zone Neurogenic Niche

Several microRNAs (miRNAs) that are either specifically enriched or highly expressed in neurons and glia have been described, but the identification of miRNAs modulating neural stem cell (NSC) biology remains elusive. In this study, we exploited high throughput miRNA expression profiling to identify candidate miRNAs enriched in NSC/early progenitors derived from the murine subventricular zone (SVZ). Then, we used lentiviral miRNA sensor vectors (LV.miRT) to monitor the activity of shortlisted miRNAs with cellular and temporal resolution during NSC differentiation, taking advantage of in vitro and in vivo models that recapitulate physiological neurogenesis and gliogenesis and using known neuronal- and glial-specific miRNAs as reference. The LV.miRT platform allowed us monitoring endogenous miRNA activity in low represented cell populations within a bulk culture or within the complexity of CNS tissue, with high sensitivity and specificity. In this way we validated and extended previous results on the neuronal-specific miR-124 and the astroglial-specific miR-23a. Importantly, we describe for the first time a cell type- and differentiation stage-specific modulation of miR-93 and miR-125b in SVZ-derived NSC cultures and in the SVZ neurogenic niche in vivo, suggesting key roles of these miRNAs in regulating NSC function.

Polymeric Nanoparticles to Control the Differentiation of Neural Stem Cells in the Subventricular Zone of the Brain

Herein, we report the use of retinoic acid-loaded polymeric nanoparticles as a potent tool to induce the neuronal differentiation of subventricular zone neural stem cells. The intracellular delivery of retinoic acid by the nanoparticles activated nuclear retinoic acid receptors, decreased stemness, and increased proneurogenic gene expression. Importantly, this work reports for the first time a nanoparticle formulation able to modulate in vivo the subventricular zone neurogenic niche. The work further compares the dynamics of initial stages of differentiation between SVZ cells treated with retinoic acid-loaded polymeric nanoparticles and solubilized retinoic acid. The nanoparticle formulation developed here may ultimately offer new perspectives to treat neurodegenerative diseases.

Fractone-heparan sulfates mediate BMP-7 inhibition of cell proliferation in the adult subventricular zone

Bone morphogenetic protein-7 (BMP-7) is a heparin-binding growth factor that inhibits cell proliferation in the subventricular zone (SVZ) of the lateral ventricle, the primary neurogenic niche in the adult brain. However, the physiological mechanisms regulating the activity of BMP-7 in the SVZ are unknown. Here, we report the inhibitory effect of BMP-7 on cell proliferation through the anterior SVZ after intracerebroventricular injection in the adult mouse. To determine whether the inhibition of cell proliferation induced by BMP-7 is dependant on heparin-binding, heparitinase-1 was intracerebroventricularly injected to N-desulfate heparan sulfate proteoglycans before BMP-7 was injected. Heparatinase-1 drastically reduced the inhibitory effect of BMP-7 on cell proliferation in the SVZ. To determine where BMP-7 binds within the niche, we visualized biotinylated-BMP-7 after intracerebroventricular injection, using streptavidin Texas red on frozen brain sections. BMP-7 binding was seen as puncta in the SVZ at the location of fractones, the particulate specialized extracellular matrix of the SVZ, which have been identified primarily by N-sulfated heparan sulfate immunoreactivity (NS-HS+). BMP binding was also seen in NS-HS+ blood vessels of the SVZ. Injection of heparitinase-1 prior to biotinylated BMP-7 resulted in the absence of signal for biotinylated-BMP-7 in the fractones and blood vessels, indicating that the binding is heparan sulfate dependant. These results indicate that BMP-7 requires heparan sulfates to bind and inhibit cell proliferation in the SVZ neurogenic niche. Heparan sulfates concentrated in fractones and SVZ blood vessels emerge as a functional stem cell niche component involved in growth factor activity.

An Endogenous Vitamin K-Dependent Mechanism Regulates Cell Proliferation in the Brain Subventricular Stem Cell Niche

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