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1.
Neurochem Int ; 126: 69-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30851365

RESUMO

Neurogenesis and angiogenesis share regulatory factors that contribute to the formation of vascular networks and neuronal circuits in the brain. While crosstalk mechanisms between neural stem cells (NSCs) and the vasculature have been extensively investigated, recent studies have provided evidence that blood vessels also play an essential role in neuronal migration in the brain during development and regeneration. The mechanisms of the neuronal migration along blood vessels, referred to as "vascular-guided migration," are now being elucidated. The vascular endothelial cells secrete soluble factors that attract and promote neuronal migration in collaboration with astrocytes that enwrap the blood vessels. In addition, especially in the adult brain, the blood vessels serve as a migration scaffold for adult-born immature neurons generated in the ventricular-subventricular zone (V-SVZ), a germinal zone surrounding the lateral ventricles. The V-SVZ-derived immature neurons use the vascular scaffold to assist their migration toward an injured area after ischemic stroke, and contribute to neuronal regeneration. Here we review the current knowledge about the role of vasculature in neuronal migration and the molecular mechanisms controlling this process. While most of this research has been done in rodents, a comprehensive understanding of vasculature-guided neuronal migration could contribute to new therapeutic approaches for increasing new neurons in the brain after injury.

2.
Mol Biol Cell ; : mbcE18050286, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30379609

RESUMO

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 the niche. Here, we examined the molecular compositions and functions of BMs in the adult mouse V-SVZ. Whole-mount V-SVZ immunostaining revealed that fractones, which are finger-like 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 decreased number and size of speckled BMs and reduced in vitro neurosphere-forming activity. Our results reveal niche activities of fractones/speckled BMs for NSCs and provide molecular insights into how laminin-integrin interactions regulate NSCs in vivo. [Media: see text].

3.
Cell Rep ; 25(3): 624-639.e6, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332643

RESUMO

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 process extension, which propels the migration of olfactory interneurons during olfactory bulb formation.

4.
J Dermatol ; 45(8): 963-970, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29897137

RESUMO

Little attention has been given to the burden of chronic urticaria (CU) in Japan compared with other skin diseases, such as atopic dermatitis (AD) and psoriasis. The primary objective of the RELEASE study was to evaluate the real-life quality-of-life impairment in CU patients in Japan. Data were collected from 1443 urticaria, 1668 AD and 435 psoriatic patients; 552 urticaria patients who presented urticaria symptoms for over 6 weeks were defined as CU. The mean Dermatology Life Quality Index (DLQI) total score was 4.8, 6.1 and 4.8 in CU, AD and psoriatic patients, respectively. Disease control of urticaria evaluated by the Urticaria Control Test (UCT) and DLQI exhibited a strong correlation with a Spearman's rank correlation coefficient of -0.7158. CU and AD patients had relatively higher scores in all Work Productivity and Activity Impairment - General Health subscales except for absenteeism. At the time of the survey, approximately 64% of CU patients reported UCT scores of <12 and demonstrated higher work productivity loss and activity impairment versus patients with UCT scores of ≥12. Patients with lower UCT scores also displayed a higher percentage of dissatisfaction with their health state and the treatment they received. Approximately 85% of patients with CU had visited dermatology clinics, and less than 20% had visited hospital, indicating existence of a highly burdened population outside specialized centers. These results highlight the unmet medical needs of CU patients, suggesting the need to increase awareness of CU burden among both physicians and patients and to pursue improved real-life patient care.

5.
Cell Stem Cell ; 22(6): 783-784, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859165

RESUMO

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.

6.
J Neurosci ; 38(19): 4598-4609, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29661967

RESUMO

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 in vivo 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 sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB.SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell-cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain.

7.
Cell Stem Cell ; 22(1): 128-137.e9, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276142

RESUMO

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 injury, thereby enhancing neuronal regeneration and functional recovery from neonatal brain injuries.

8.
Stem Cell Reports ; 9(1): 203-216, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28648897

RESUMO

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, [3H]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, which is useful for identifying these primary progenitors and study their gene regulation.


Assuntos
Ventrículos Laterais/citologia , Células-Tronco Neurais/citologia , Membrana Nuclear/ultraestrutura , Células-Tronco Adultas/citologia , Animais , Astrócitos/citologia , Ciclo Celular , Células Cultivadas , Cromatina/química , Camundongos
9.
Adv Healthc Mater ; 6(11)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28488337

RESUMO

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 immobilize VEGF is a practical approach for developing angiogenic biomaterials for regenerating the injured brain.


Assuntos
Isquemia Encefálica , Proteínas Imobilizadas , Laminina , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Implantes de Medicamento/química , Implantes de Medicamento/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/farmacologia , Laminina/química , Laminina/farmacologia , Camundongos , Porosidade , Fator A de Crescimento do Endotélio Vascular/farmacologia
10.
J Neurochem ; 141(6): 835-847, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28251650

RESUMO

Adult neurogenesis was first observed nearly 60 years ago, and it has since grown into an important neurochemistry research field. Much recent research has focused on the treatment of brain diseases through neuronal regeneration with endogenously generated neurons. In the adult brain, immature neurons called neuroblasts are continuously generated in the ventricular-subventricular zone (V-SVZ). These neuroblasts migrate rapidly through the rostral migratory stream to the olfactory bulb, where they mature and are integrated into the neuronal circuitry. After brain insult, some of the neuroblasts in the V-SVZ migrate toward the lesion to repopulate the injured tissue. This notable migratory capacity of V-SVZ-derived neuroblasts is important for efficiently regenerating neurons in remote areas of the brain. As these neurons migrate for long distances through adult brain tissue, they are supported by various guidance cues and structures that act as scaffolds. Some of these mechanisms are unique to neuroblast migration in the adult brain, and are not involved in migration in the developing brain. Here, we review the latest findings on the mechanisms of neuroblast migration in the adult brain under physiological and pathological conditions, and discuss various issues that still need to be resolved. This article is part of the mini review series "60th Anniversary of the Japanese Society for Neurochemistry".


Assuntos
Encéfalo/crescimento & desenvolvimento , Movimento Celular/fisiologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Animais , Mapeamento Encefálico , Humanos
11.
EBioMedicine ; 16: 195-203, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28153772

RESUMO

Cerebral ischemic stroke is a main cause of chronic disability. However, there is currently no effective treatment to promote recovery from stroke-induced neurological symptoms. Recent studies suggest that after stroke, immature neurons, referred to as neuroblasts, generated in a neurogenic niche, the ventricular-subventricular zone, migrate toward the injured area, where they differentiate into mature neurons. Interventions that increase the number of neuroblasts distributed at and around the lesion facilitate neuronal repair in rodent models for ischemic stroke, suggesting that promoting neuroblast migration in the post-stroke brain could improve efficient neuronal regeneration. To move toward the lesion, neuroblasts form chain-like aggregates and migrate along blood vessels, which are thought to increase their migration efficiency. However, the molecular mechanisms regulating these migration processes are largely unknown. Here we studied the role of ß1-class integrins, transmembrane receptors for extracellular matrix proteins, in these migrating neuroblasts. We found that the neuroblast chain formation and blood vessel-guided migration critically depend on ß1 integrin signaling. ß1 integrin facilitated the adhesion of neuroblasts to laminin and the efficient translocation of their soma during migration. Moreover, artificial laminin-containing scaffolds promoted neuroblast chain formation and migration toward the injured area. These data suggest that laminin signaling via ß1 integrin supports vasculature-guided neuronal migration to efficiently supply neuroblasts to injured areas. This study also highlights the importance of vascular scaffolds for cell migration in development and regeneration.


Assuntos
Encéfalo/metabolismo , Movimento Celular , Integrina beta1/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Vasos Sanguíneos/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/ultraestrutura , Células Cultivadas , Técnicas de Cocultura , Feminino , Integrina beta1/genética , Laminina/metabolismo , Masculino , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Acidente Vascular Cerebral/metabolismo , Tecidos Suporte
12.
PLoS One ; 11(10): e0164418, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27723809

RESUMO

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 regression analysis showed that rs1863918 T allele, a history of depression, and younger age were independent predictive factors for IFN-induced depression. Interestingly, western blotting and immunofluorescence showed that ZNF354C was highly expressed in the hippocampus in mice, a region implicated in the pathology of psychiatric symptoms. In conclusion, we identified rs1863918 as significantly associated with IFN-induced depression, and revealed that the candidate gene ZNF354C is highly expressed in the hippocampus of mice. Our data might be useful for elucidating the pathogenic mechanisms of depression induced by drugs including IFN.


Assuntos
Cromossomos Humanos Par 5/genética , Depressão , Estudo de Associação Genômica Ampla , Hepatite C Crônica , Interferon-alfa/efeitos adversos , Desequilíbrio de Ligação , Polietilenoglicóis/efeitos adversos , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Adulto , Idoso , Animais , Depressão/induzido quimicamente , Depressão/genética , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interferon-alfa/administração & dosagem , Masculino , Camundongos , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos
13.
J Comp Neurol ; 524(15): 2982-92, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-26991819

RESUMO

In mammals, ventricular walls of the developing brain maintain a neurogenic niche, in which radial glial cells act as neural stem cells (NSCs) and generate new neurons in the embryo. In the adult brain, the neurogenic niche is maintained in the ventricular-subventricular zone (V-SVZ) of the lateral wall of lateral ventricles and the hippocampal dentate gyrus. In the neonatal V-SVZ, radial glial cells transform into astrocytic postnatal NSCs and multiciliated ependymal cells. On the other hand, in zebrafish, radial glial cells continue to cover the surface of the adult telencephalic ventricle and maintain a higher neurogenic potential in the adult brain. However, the cell composition of the neurogenic niche of the aged zebrafish brain has not been investigated. Here we show that multiciliated ependymal cells emerge in the neurogenic niche of the aged zebrafish telencephalon. These multiciliated cells appear predominantly in the dorsal part of the ventral telencephalic ventricular zone, which also contains clusters of migrating new neurons. Scanning electron microscopy and live imaging analyses indicated that these multiple cilia beat coordinately and generate constant fluid flow within the ventral telencephalic ventricle. Analysis of the cell composition by transmission electron microscopy revealed that the neurogenic niche in the aged zebrafish contains different types of cells, with ultrastructures similar to those of ependymal cells, transit-amplifying cells, and migrating new neurons in postnatal mice. These data suggest that the transformation capacity of radial glial cells is conserved but that its timing is different between fish and mice. J. Comp. Neurol. 524:2982-2992, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Envelhecimento/fisiologia , Epêndima/citologia , Nicho de Células-Tronco/fisiologia , Telencéfalo/citologia , Peixe-Zebra/fisiologia , Envelhecimento/patologia , Animais , Animais Geneticamente Modificados , Movimento Celular/fisiologia , Cílios/ultraestrutura , Epêndima/crescimento & desenvolvimento , Epêndima/fisiologia , Epêndima/ultraestrutura , Imuno-Histoquímica , Microscopia Confocal , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Telencéfalo/crescimento & desenvolvimento , Telencéfalo/fisiologia , Telencéfalo/ultraestrutura , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/crescimento & desenvolvimento
14.
Pharmacogenomics ; 16(3): 217-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25712185

RESUMO

AIM: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African-Americans. METHODS: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African-Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African-Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. RESULTS: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m(2)/-10 kg reduction in CL[S], respectively) in African-Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. CONCLUSION: African-Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014.


Assuntos
Afro-Americanos/genética , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Anticoagulantes/sangue , Superfície Corporal , Peso Corporal , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Vitamina K Epóxido Redutases/genética , Varfarina/sangue
15.
Front Cell Neurosci ; 9: 5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25674053

RESUMO

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 and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

16.
Nihon Rinsho ; 73 Suppl 5: 210-4, 2015 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-30457801
17.
Stem Cell Reports ; 3(1): 73-84, 2014 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-25068123

RESUMO

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 new strategies for the prevention and treatment of IFN-α-induced depressive effects.


Assuntos
Depressão/induzido quimicamente , Interferon-alfa/efeitos adversos , Células-Tronco Neurais/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Depressão/metabolismo , Depressão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/efeitos dos fármacos
18.
Front Cell Neurosci ; 7: 235, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24348331

RESUMO

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 and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine.

19.
Stroke ; 44(2): 551-4, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23238858

RESUMO

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 the expression of proinflammatory cytokines, increased the expression of anti-inflammatory ones, and significantly reduced apoptosis. Notably, the intracerebral administration of SHED-conditioned medium also significantly improved the neurological outcome, inhibited apoptosis, and reduced tissue loss. CONCLUSIONS: SHED transplantation into the HI-injured brain resulted in remarkable neurological and pathophysiological recovery. Our findings indicate that paracrine factors derived from SHED support a neuroprotective microenvironment in the HI brain. SHED graft and SHED-conditioned medium may provide a novel neuroprotective therapy for HI.


Assuntos
Lesões Encefálicas/cirurgia , Polpa Dentária/citologia , Polpa Dentária/transplante , Hipóxia-Isquemia Encefálica/cirurgia , Transplante de Células-Tronco/métodos , Animais , Animais Recém-Nascidos , Lesões Encefálicas/patologia , Células Cultivadas , Humanos , Hipóxia-Isquemia Encefálica/patologia , Camundongos
20.
PLoS One ; 7(11): e48431, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23133633

RESUMO

Sensory input is essential for the normal development of sensory centers in the brain, such as the somatosensory, visual, auditory, and olfactory systems. Visual deprivation during a specific developmental stage, called the critical period, results in severe and irreversible functional impairments in the primary visual cortex. Olfactory deprivation in the early postnatal period also causes significant developmental defects in the olfactory bulb, the primary center for olfaction. Olfactory bulb interneurons are continuously generated from neural stem cells in the ventricular-subventricular zone, suggesting that the olfactory system has plasticity even in adulthood. Here, we investigated the effect of transient neonatal olfactory deprivation on the addition of interneurons to the glomerular layer of the adult mouse olfactory bulb. We found that the addition of one subtype of interneurons was persistently inhibited even after reopening the naris. BrdU pulse-chase experiments revealed that the neonatal olfactory deprivation predominantly affected an early phase in the maturation of this neuronal subtype in the olfactory bulb. Subjecting the mice to odor stimulation for 6 weeks after naris reopening resulted in significant recovery from the histological and functional defects caused by the olfactory deprivation. These results suggest that a subtype-specific critical period exists for olfactory bulb neurogenesis, but that this period is less strict and more plastic compared with the critical periods for other systems. This study provides new insights into the mechanisms of postnatal neurogenesis and a biological basis for the therapeutic effect of olfactory training.


Assuntos
Neurogênese/fisiologia , Bulbo Olfatório/patologia , Olfato/fisiologia , Animais , Bromodesoxiuridina/farmacologia , Núcleo Celular/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Odorantes , Privação Sensorial/fisiologia , Córtex Visual/fisiologia
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