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Additional file 3: Data S3. Details of statistical analysis for Fig. 4
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Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue... more
Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue growth and repair. Proangiogenic therapy for stroke is promising for preventing excess neuron death and improving functional recovery. Vascular endothelial growth factor (VEGF) is a critical factor for angiogenesis by promoting the proliferation, the survival, and the migration of endothelial cells. Here, angiogenic biomaterials to support injured brain regeneration are developed. Porous laminin (LN)‐rich sponge (LN‐sponge), on which histidine‐tagged VEGF (VEGF‐Histag) is immobilized via affinity interaction is developed. In an in vivo mouse stroke model, transplanting VEGF‐Histag‐LN‐sponge produces remarkably stronger angiogenic activity than transplanting LN‐sponge with soluble VEGF. The findings indicate that using affinity interactions to immobil...
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ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory... more
ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.
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Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and they reside in specific areas. Cultures of NSCs can be successfully established in vitro by exploiting the NeuroSphere assay. This methodology... more
Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and they reside in specific areas. Cultures of NSCs can be successfully established in vitro by exploiting the NeuroSphere assay. This methodology relies on the continuous exposure of neural cells to mitogens such as epidermal growth factor and fibroblast growth factor-2. Under these conditions, only NSCs and highly undifferentiated progenitors proliferate, whereas committed precursors and terminally differentiated cells are eliminated from the culture. The proper application of this method to the cells allows the establishment of long-term expanding stable NSC lines, starting from different neural tissues as the adult rodent CNS and human brain tumor specimens.
Research Interests: Stem Cells, Biology, Medicine, Cell separation, Rodentia, and 14 moreNeural stem cell, In Vitro, Cell Differentiation, Humans, Animals, Central Nervous System, Dissection, Neurons, Fibroblast Growth Factor, Neural Stem Cells, Biochemistry and cell biology, Neurosphere, Neoplastic Stem Cells, and Cell culture techniques
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to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migration, and neurite outgrowth of neurones. Thus, Nogo signalling is a potent endogenous inhibitor of adult CNS regeneration. Recently, we found... more
to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migration, and neurite outgrowth of neurones. Thus, Nogo signalling is a potent endogenous inhibitor of adult CNS regeneration. Recently, we found that phosphorylation of a particular serine residue on the Nogo receptor NgR inhibits ligand binding, enabling neurite outgrowth even in the presence of the inhibitory myelin-associated proteins. Our work could provide a launching point for developing methods to stimulate neuronal regeneration in the adult mammalian CNS.
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Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus... more
Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep–wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep–wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep–wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consoli...
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In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continues throughout life. Previous studies using rodents suggest that adult-born neurons are involved in memory and cognition tasks and mood... more
In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continues throughout life. Previous studies using rodents suggest that adult-born neurons are involved in memory and cognition tasks and mood regulation. Interferon-alpha (IFNα), a proinflammatory cytokine used for the treatment of chronic viral hepatitis and malignancies, frequently causes depressive symptoms in patients and animals, including non-human primates. We have previously demonstrated that chronic IFNα treatment decreases hippocampal neurogenesis in mice. Here, we investigated the effects of four-week human pegylated IFNα treatment on hippocampal neurogenesis and behavior in common marmosets. Continuous monitoring of voluntary activity levels using an actigraphy device suggested that adaptive ability is impaired in IFNα-treated animals. Analyses of BrdU-labeled cells expressing a marker for immature or mature neurons revealed a significant reduction in the number of new neurons in th...
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In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream... more
In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustai...
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Adult neural stem cells in the wall of brain ventricles make direct contact with cerebrospinal fluid. In this issue of Cell Stem Cell, Petrik et al. (2018) demonstrate that these neural stem cells sense the flow of cerebrospinal fluid... more
Adult neural stem cells in the wall of brain ventricles make direct contact with cerebrospinal fluid. In this issue of Cell Stem Cell, Petrik et al. (2018) demonstrate that these neural stem cells sense the flow of cerebrospinal fluid through a transmembrane sodium channel, ENaC, which regulates their proliferation.
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As an essential step for brain morphogenesis, neurons migrate via mechanical interactions with components of their environment such as neighboring cells and the extracellular matrix. However, the molecular mechanism by which neurons exert... more
As an essential step for brain morphogenesis, neurons migrate via mechanical interactions with components of their environment such as neighboring cells and the extracellular matrix. However, the molecular mechanism by which neurons exert forces on their environment during migration remains poorly understood. Here, we show that shootin1b is expressed in migrating mouse olfactory interneurons and accumulates at their leading process growth cone. We demonstrate that shootin1b, by binding to cortactin and L1-CAM, couples F-actin retrograde flow and the adhesive substrate as a clutch molecule. Shootin1b-mediated clutch coupling at the growth cone generates traction force on the substrate, thereby promoting leading process extension and subsequent somal translocation of olfactory interneurons. Furthermore, loss of shootin1 causes abnormal positioning of the interneurons and dysgenesis of the olfactory bulb. Our findings indicate that shootin1b plays a key role in force-driven leading pro...
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Appropriate positioning of new neurons in the brain promotes post-stroke functional recovery.
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Neural stem cells (NSCs) are retained in the adult ventricular–subventricular zone (V-SVZ), a specialized neurogenic niche with a unique cellular architecture. It currently remains unclear whether or how NSCs utilize basement membranes... more
Neural stem cells (NSCs) are retained in the adult ventricular–subventricular zone (V-SVZ), a specialized neurogenic niche with a unique cellular architecture. It currently remains unclear whether or how NSCs utilize basement membranes (BMs) in this niche. Here, we examine the molecular compositions and functions of BMs in the adult mouse V-SVZ. Whole-mount V-SVZ immunostaining revealed that fractones, which are fingerlike processes of extravascular BMs, are speckled BMs unconnected to the vasculature, and differ in their molecular composition from vascular BMs. Glial fibrillary acidic protein (GFAP)-positive astrocytes and NSCs produce and adhere to speckled BMs. Furthermore, Gfap-Cre-mediated Lamc1flox(E1605Q) knockin mice, in which integrin-binding activities of laminins are specifically nullified in GFAP-positive cells, exhibit a decreased number and size of speckled BMs and reduced in vitro neurosphere-forming activity. Our results reveal niche activities of fractones/speckled ...
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Radial glia (RG) are embryonic neural stem cells (NSCs) that produce neuroblasts and provide fibers that act as a scaffold for neuroblast migration during embryonic development. Although they normally disappear soon after birth, here we... more
Radial glia (RG) are embryonic neural stem cells (NSCs) that produce neuroblasts and provide fibers that act as a scaffold for neuroblast migration during embryonic development. Although they normally disappear soon after birth, here we found that RG fibers can persist in injured neonatal mouse brains and act as a scaffold for postnatal ventricular-subventricular zone (V-SVZ)-derived neuroblasts that migrate to the lesion site. This injury-induced maintenance of RG fibers has a limited time window during post-natal development and promotes directional saltatory movement of neuroblasts via N-cadherin-mediated cell-cell contacts that promote RhoA activation. Transplanting an N-cadherin-containing scaffold into injured neonatal brains likewise promotes migration and maturation of V-SVZ-derived neuroblasts, leading to functional improvements in impaired gait behaviors. Together these results suggest that RG fibers enable postnatal V-SVZ-derived neuroblasts to migrate toward sites of inj...
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Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function... more
Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [(3)H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, whic...
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The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224... more
The therapeutic use of interferon (IFN) is known to cause depression that frequently interrupts treatment. To identify genetic variants associated with IFN-induced depression, we conducted a genome-wide association study (GWAS) of 224 Japanese chronic hepatitis C patients receiving IFN-based therapy in a multicenter prospective study and stratified them into two groups according to the Beck Depression Inventory, Second Edition (BDI-II) score. In the GWAS stage, we selected 42 candidate single nucleotide polymorphisms (SNPs) to perform replication analysis in an independent set of 160 subjects. The SNP rs1863918 in strong linkage disequilibrium with SNPs located around the Zinc finger 354C (ZNF354C) gene on chromosome 5 showed a significant association when the results of GWAS and replication were combined (odds ratio = 2.55, P = 7.89×10-8 in the allele frequency model), suggesting that the rs1863918 T allele was associated with IFN-induced depression. Furthermore, logistic regressio...
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Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term... more
Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects an...
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New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α... more
New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing ...
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Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells... more
Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells and induced-pluripotent stem cells. Although the transplantation of these exogenous NSCs is a potential strategy for improving presently untreatable neurological conditions, there are several obstacles to its implementation, including tumorigenic, immunological, and ethical problems. Recent studies have revealed that NSCs also reside in the adult brain. The endogenous NSCs are activated in response to disease or trauma, and produce new neurons and glia, suggesting they have the potential to regenerate damaged brain tissue while avoiding the above-mentioned problems. Here we present an overview of the possibility and limitations of using endogenous NSCs in regenerative medicine.
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Currently, there is no effective treatment for the marked neuronal loss caused by neurodegenerative diseases, such as Huntington's disease (HD) or ischemic stroke. However, recent studies have shown that new neurons are continuously... more
Currently, there is no effective treatment for the marked neuronal loss caused by neurodegenerative diseases, such as Huntington's disease (HD) or ischemic stroke. However, recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain, including the human brain. Because some of these new neurons migrate to the injured striatum and differentiate into mature neurons, such new neurons may be able to replace degenerated neurons and improve or repair neurological deficits. To establish a neuroregenerative therapy using this endogenous system, endogenous regulatory mechanisms that can be co-opted for efficient regenerative interventions must be understood, along with any potential drawbacks. Here, we review current knowledge on the generation of new neurons in the adult brain and discuss their potential for use in replacing striatal neurons lost to neurodegenerative diseases, includin...
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To examine the role of immune complexes in the prostanoid metabolism of glomerular capillary endothelial cells (EC) and platelets in lupus nephritis. Heat aggregated IgG (HA-IgG), instead of immune complexes, was incubated using an in... more
To examine the role of immune complexes in the prostanoid metabolism of glomerular capillary endothelial cells (EC) and platelets in lupus nephritis. Heat aggregated IgG (HA-IgG), instead of immune complexes, was incubated using an in vitro coculture system with human umbilical vein EC, instead of glomerular capillary EC, and platelets. The effect of complement component C1q and a novel imidazole-type thromboxane A2 (TXA2) synthetase inhibitor, DP-1904, on this prostanoid metabolism change was also investigated. EC monolayers (1.5x10(5) cells/well) were incubated with various concentrations of HA-IgG, monomeric IgG, or medium alone for 1 h at 37 degrees C, and then incubated with platelet suspensions (1x10(8) cells/ml) for various times. Concentrations of TXB2 and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), the stable hydrolysis products of TXA2 and prostaglandin I2 (PGI2), respectively, released in the supernatants were measured by ELISA. HA-IgG bound to EC monolayers prod...
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Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and... more
Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and differentiate into mature neurons, suggesting that such new neurons may be able to replace neurons lost to degenerative disease or injury and improve or repair neurological deficits. Here, we tested whether delivering growth factors via gelatin hydrogel microspheres would support neurogenesis in the SVZ. Insulin-like growth factor-1 (IGF-1)-containing microspheres increased the number of new neurons in the SVZ. Hepatocyte growth factor (HGF)-containing microspheres increased the number of new neurons migrating from the SVZ towards the injured striatum in a stroke model in mouse. These results suggest that the strategy of using gelatin hydrogel microspheres to achieve the sustained release of growth factors holds promise for the clinical regeneration of damage...
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Background and Purpose— Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects... more
Background and Purpose— Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury. Methods— Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these cells was injected into the injured brain. The effects of cell transplantation or conditioned medium injection on the animals’ neurological and pathophysiological recovery were evaluated. Results— Transplanted SHED, but not fibroblasts, significantly reduced the HI-induced brain-tissue loss and improved neurological function. SHED also improved the survival of the HI mice. The engrafted SHED rarely differentiated into neural lineages; however, their transplantation inhibited th...
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Research Interests: Cognitive Science, Nonparametric Statistics, Biology, Medicine, Brain, and 15 moreNeuropeptides, Mice, Animals, Astrocyte, Neurons, Astrocytes, Amino Acids, Neuron, Glial Fibrillary Acidic Protein, Transfection, Neurosciences, Organic Chemicals, Gene Expression Regulation, Cell count, and coculture techniques
Research Interests: Neuroscience, Cognitive Science, Biology, Enzyme Inhibitors, Medicine, and 15 moreBrain development, Nature, Neuropeptides, Mice, Animals, Nature Neuroscience, Actin Dynamics, Amides, Analysis of Variance, Neuronal Migration, Neural Stem Cells, Neurosciences, Interneurons, Glutamate decarboxylase, and Extracellular Matrix Proteins
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Inflammatory markers such as the C-reactive protein (CRP), white blood cell count and body temperature are easy to measure and are used as indicators of infection. The way in which they change in the early post-operative period after... more
Inflammatory markers such as the C-reactive protein (CRP), white blood cell count and body temperature are easy to measure and are used as indicators of infection. The way in which they change in the early post-operative period after instrumented spinal surgery has not been reported in any depth. We measured these markers pre-operatively and at one, four, seven and 14 days postoperatively in 143 patients who had undergone an instrumented posterior lumbar interbody fusion. The CRP proved to be the only sensitive marker and had returned to its normal level in 48% of patients after 14 days. The CRP on day 7 was never higher than that on day 4. Age, gender, body temperature, operating time and blood loss were not related to the CRP level. A high CRP does not in itself suggest infection, but any increase after four days may presage infection.
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In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is... more
In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ an...