Details of a Researcher - Okano, Hideyuki

Papers - Okano, Hideyuki

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Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury

Ikegami Takeshi, Nakamura Masaya, Yamane Junichi, Katoh Hiroyuki, Okada Seiji, Iwanami Akio, Watanabe Kota, Ishii Ken, Kato Fumikazu, Fujita Hiroshi, Takahashi Toyomi, Okano Hirotaka James, Toyama Yoshiaki, Okano Hideyuki

European Journal of Neuroscience 22 ( 12 ) 3036 - 3046 2005.12

ISSN 0953-816X

We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord. © Federation of European Neuroscience Societies.

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Downregulation of Notch, mediated by numb and -adaptin, is required for the differentiation of postembryonic neural stem cells in Drosophila

Nakao, Keiko, Toriya, Masako, Orihara, Minako, Takahashi, Miwa, Okano, Hideyuki

ZOOLOGICAL SCIENCE 22 ( 12 ) 1468 - 1468 2005.12

Research paper (scientific journal), ISSN 0289-0003

Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity

Kanuka Hirotaka, Hiratou Tetsuo, Igaki Tatsushi, Kanda Hiroshi, Kuranaga Erina, Sawamoto Kazunobu, Aigaki Toshiro, Okano Hideyuki, Miura Masayuki

Biochimica et Biophysica Acta - General Subjects 1726 ( 3 ) 225 - 237 2005.11

ISSN 0304-4165

To elucidate the intrinsic mechanisms of neurotoxicity induction, including those underlying neural cell death and neurodegeneration, we developed a gain-of-function screen for gene products causing neural cell loss. To identify novel genes with a cell-death-related function in neurons, we screened 4,964 Drosophila GS lines, in which one or two genes from much of the Drosophila genome can be overexpressed. Approximately 0.68% of the GS lines produced phenotypes involving a loss of postmitotic neurons. Of these, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61α (DSec61α), an endoplasmic reticulum protein with protein translocation activity. Ectopic expression of DSec61α caused neural cell death accompanied by the accumulation of ubiquitinated proteins, which was mediated by DSec61α's translocon activity. This supported our previous observation that the DSec61α translocon contributes to expanded polyglutamine-mediated neuronal toxicity, which is also associated with ubiquitinated protein accumulation. These data suggest that the translocon may be a novel component of neural cell death and degeneration pathways. Our approach can be used to identify potential neurotoxic factors within the whole genome, which will increase our understanding of the molecular mechanisms of various types of cell death, including those associated with human neurodegenerative diseases. © 2005 Elsevier B.V. All rights reserved.

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Hzf protein regulates dendritic localization and BDNF-induced translation of type 1 inositol 1,4,5-trisphosphate receptor mRNA

Iijima Takatoshi, Imai Takao, Kimura Yuki, Bernstein Alan, Okano Hirotaka James, Yuzaki Michisuke, Okano Hideyuki

Proceedings of the National Academy of Sciences of the United States of America 102 ( 47 ) 17190 - 17195 2005.11

ISSN 0027-8424

The localization of certain mRNAs to dendrites and their local translation in synaptic regions are proposed to be involved in certain aspects of synaptic plasticity. A cis-acting element within the 3′ untranslated region (3′ UTR) of the targeted mRNAs, which is bound by a trans-acting RNA-binding protein, controls the dendritic mRNA localization. Here, we identified hematopoietic zinc finger (Hzf) as a trans-acting factor that regulates the dendritic mRNA localization of the type 1 inositol 1,4,5-trisphosphate receptor (IP₃RI), a dendritically localized mRNA in cerebellar Purkinje cells, via binding to the 3′ UTR. In Hzf-deficient mice, the dendritic localization of IP₃RI mRNA and brain-derived neurotrophic factor-induced IP₃RI protein synthesis in the cerebellum were impaired. These findings suggest that Hzf is an RNA-binding protein that controls the dendritic mRNA localization and activity-dependent translation of IP₃RI, and may be involved in some aspects of synaptic plasticity. © 2005 by The National Academy of Sciences of the USA.

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Drosophila caspase transduces Shaggy/GSK-3β kinase activity in neural precursor development

Kanuka Hirotaka, Kuranaga Erina, Takemoto Kiwamu, Hiratou Tetsuo, Okano Hideyuki, Miura Masayuki

EMBO Journal 24 ( 21 ) 3793 - 3806 2005.11

ISSN 0261-4189

All Rights Reserved.Caspases are well known for their role in the execution of apoptotic programs, in which they cleave specific target proteins, leading to the elimination of cells, and for their role in cytokine maturation. In this study, we identified a novel substrate, which, through cleavage by caspases, can regulate Drosophila neural precursor development. Shaggy (Sgg)46 protein, an isoform encoded by the sgg gene and essential for the negative regulation of Wingless signaling, is cleaved by the Dark-dependent caspase. This cleavage converts it to an active kinase, which contributes to the formation of neural precursor (sensory organ precursor (SOP)) cells. Our evidence suggests that caspase regulation of the wingless pathway is not associated with apoptotic cell death. These results imply a novel role for caspases in modulating cell signaling pathways through substrate cleavage in neural precursor development. © 2005 European Molecular Biology Organization

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Essential role of Shp2-binding sites on FRS2α for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells

Yamamoto S., Yoshino I., Shimazaki T., Murohashi M., Hevner R. F., Lax I., Okano H., Shibuya M., Schlessinger J., Gotoh N.

Proceedings of the National Academy of Sciences of the United States of America 102 ( 44 ) 15983 - 15988 2005.11

ISSN 0027-8424

Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2α is a major mediator of signaling by means of FGFs and neurotrophins. FRS2α mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2α leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2α plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2α mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2α play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation. © 2005 by The National Academy of Sciences of the USA.

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Transplantation of neural stem cells for spinal cord injury

Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

Clinical Neurology 45 ( 11 ) 874 - 876 2005.11

ISSN 0009-918X

Neural progenitor cells, including neural stem cells (NSCs), are an important potential graft material for cell therapeutics of damaged spinal cord. Here we used as a source of graft material a NSC-enriched population derived from human fetal spinal cord (Embryonic week 8-9) and expanded in vitro by neurosphere formation. NSCs labeled with BrdU (TP) or culture medium (CON) were transplanted into the adult marmoset spinal cord after contusion injury at C5 level. Grafted NSCs survived and migrated up to 7 mm far from the lesion epicenter. Double-staining with TuJ1 for neuron, GFAP for astrocyte, or CNPase for oligodendrocyte and BrdU revealed that grafted NSCs differentiated into neurons and oligodendrocytes 8 weeks after transplantation. More neurofilaments were observed in TP than those of CON. Furthermore, behavioral assessment of forelimb muscle strength using bar grip test and amount of spontaneous motor activity using infrared-rays monitoring revealed that the grafted NSCs significantly increased both of them compared to those of CON. These results indicate that in vitro expanded NSCs derived from human fetal spinal cord are useful sources for the therapeutics of spinal cord injury in primates.

An epidural cooling catheter protects the spinal cord against ischemic injury in pigs

Mori Atsuo, Ueda Toshihiko, Hachiya Takashi, Kabei Nobuyuki, Okano Hideyuki, Yozu Ryohei, Sasaki Tatsuumi

Annals of Thoracic Surgery 80 ( 5 ) 1829 - 1833 2005.11

ISSN 0003-4975

Background. Using swine, we investigated whether epidural placement of a cooling catheter rather than infusing iced saline solution could protect the spinal cord from ischemia during aortic surgery. Methods. We divided 14 domestic pigs into two groups of 7 each. Each underwent epidural catheter placement preceding 30 minutes of aortic cross-clamping distal to the origin of the left subclavian artery. In group 1, cold water was circulated continuously through the lumen of the catheter connected to an external unit. In group 2, animals received catheter placement without cooling. Spinal cord somatosensory evoked potentials were recorded. Neurologic status involving hind limbs was graded sequentially after surgery. Results. At aortic cross-clamping, spinal temperature in group 1 (31.7° ± 0.6°C) was significantly lower than in group 2 (37.8° ± 0.4°C; p < 0.0001). No significant elevation of intrathecal pressure accompanied cooling with the catheter (group 1, 8.1 ± 1.7 mm Hg; group 2, 8.0 ± 1.5 mm Hg). Mean duration of total loss of potentials was significantly shorter in group 1 (7.4 ± 3.8 minutes) than group 2 (19.7 ± 7.3 minutes; p = 0.0002). Pigs in group 1 exhibited better hind limb function recovery (mean Tarlov score, 4.7 ± 0.5) than group 2 (0.6 ± 0.8; p = 0.0017). Group 1 showed normal histologic characteristics, whereas group 2 showed loss of motor neurons in the ventral horns. Conclusions. Epidural cooling catheter without iced saline infusion can cool the spinal cord without elevating intrathecal pressure, protecting the cord against ischemia. © 2005 by The Society of Thoracic Surgeons.

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Identification of neural stem cells in adult human brain

Okano Hideyuki

Clinical Neurology 45 ( 11 ) 871 - 873 2005.11

ISSN 0009-918X

Neural stem cells (NSCs) ar self-renewing, multipotential progenitor cells. A single NSC can give rise to a wide variety of CNS cells, including neurons, astrocytes, and oligodendrocytes. Because of these characteristics, there is an increasing interest in NSCs and neural progenitor cells, both from a basic developmental biology perspective and from a clinical one that is aimed at developing therapeutic applications for the damaged brain. Current research into the nature of the NSCs present in the CNS includes the study of the extracellular factors and signal transduction cascades involved in their differentiation and maintenance, their population dynamics, and their localization in the embryonic and adult brain. These lines of research, combined with other studies intended to permit the prospective identification and isolation of NSCs, and their induction into particular neuronal phenotypes-which will be introduced in my talk-should lead to the development of feasible strategies for manipulating NSC cells in situ to treat the damaged brain and spinal cord injury.

In vivo imaging of engrafted neural stem cells

Okada Seiji, Ishii Ken, Yamane Jinichi, Iwanami Akio, Ikegami Takeshi, Katoh Hiroyuki, Iwamoto Yukihide, Nakamura Masaya, Miyoshi Hiroyuki, Okano Hirotaka James, Contag Christopher H., Toyama Yoshiaki, Okano Hideyuki

FASEB Journal 19 ( 13 ) 1839 - 1841 2005.11

ISSN 0892-6638

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Neural stem cells and regeneration of injured spinal cord

Okano Hideyuki, Okada Seiji, Nakamura Masaya, Toyama Yoshiaki

Kidney International 68 ( 5 ) 1927 - 1931 2005.11

ISSN 0085-2538

Recent progress in the stem cell biology has led much insight into new therapeutic interventions aiming for the regeneration of the damaged central nervous system. The major strategies can be classified into two subgroups: (1) activation of endogenous neural stem cells, and (2) cell transplantation therapies. In either of these strategies, it is crucial to understand the underlying mechanisms of maintenance, activation, and differentiation of neural stem cells and subsequent process, including the migration, survival, and functional maturation of differentiated cells. In this paper, we would like to summarize our recent findings on the therapeutic interventions of the injured spinal cord, especially focusing on the development of treatment for the acute phase of spinal cord injury with anti-interleukin (IL)-6 receptor blocking antibody. © 2005 by the International Society of Nephrology.

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Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats

Sasaki Takahiro, Iwata Satoshi, Okano Hirotaka James, Urasaki Yasuyo, Hamada Junichi, Tanaka Hirotoshi, Dang Nam H., Okano Hideyuki, Morimoto Chikao

Stroke 36 ( 11 ) 2457 - 2462 2005.11

ISSN 0039-2499

Background and Purpose - Some proteins involved in self-repair after stroke in the adult brain are primarily expressed during embryonic development and strongly down-regulated during the early postnatal phase. Neuronal precursor cell-expressed, developmentally down-regulated gene (Nedd) 9 was recognized to be identical to Crk-associated substrate lymphocyte type (Cas-L), a docking protein that associates with a variety of signaling molecules, such as focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk. We investigated the involvement of these proteins in the pathophysiology of global cerebral ischemia. Methods - The mouse Cas-L/Nedd9 cDNAs were cloned. The expression and function of Cas-L/Nedd9 protein in the pathogenesis of global ischemia in rats was investigated by RT-PCR, Western blot analysis, and immunohistochemistry. The neurite outgrowth of the transfectants of Nedd9 deletion mutants in PC-12 cells was also assessed to clarify the function of the Nedd9 protein. Results - Nedd9 was a splicing variant of Cas-L and was selectively induced in neurons of the cerebral cortex and hippocampus 1 to 14 days after the ischemia. Induced Nedd9 protein was tyrosine phosphorylated and was bound to FAK in dendrite and soma of neurons after the ischemia. Finally, it was demonstrated that Nedd9 promoted neurite outgrowth of PC-12 cells. Conclusions - Our study may support the potential of Nedd9 for participation in the differentiation of neurons after global ischemia in rats. © 2005 American Heart Association, Inc.

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Visualization of spatiotemporal activation of Notch signaling

Kohyama Jun, Tokunaga Akinori, Fujita Yuko, Miyoshi Hiroyuki, Nagai Takeharu, Miyawaki Atsushi, Nakao Keiko, Matsuzaki Yumi, Okano Hideyuki

Developmental Biology 286 ( 1 ) 311 - 325 2005.10

ISSN 0012-1606

Notch signaling plays various key roles in cell fate determination during CNS development in a context-dependent fashion. However, its precise physiological role and the localization of its target cells remain unclear. To address this issue, we developed a new reporter system for assessing the RBP-J-mediated activation of Notch signaling target genes in living cells and tissues using a fluorescent protein Venus. Our reporter system revealed that Notch signaling is selectively activated in neurosphere-initiating multipotent neural stem cells in vitro and in radial glia in the embryonic forebrain in vivo. Furthermore, the activation of Notch signaling occurs during gliogenesis and is required in the early stage of astroglial development. Consistent with these findings, the persistent activation of Notch signaling inhibits the differentiation of GFAP-positive astrocytes. Thus, the development of our RBP-J-dependent live reporter system, which is activated upon Notch activation, together with a stage-dependent gain-of-function analysis allowed us to gain further insight into the complexity of Notch signaling in mammalian CNS development. © 2005 Elsevier Inc. All rights reserved.

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Expression of a candidate marker for progenitor cells, Musashi-1, in the proliferative regions of human antrum and its decreased expression in intestinal metaplasia

Akasaka Yoshikiyo, Saikawa Y., Fujita K., Kubota T., Ishikawa Y., Fujimoto A., Ishii T., Okano H., Kitajima M.

Histopathology 47 ( 4 ) 348 - 356 2005.10

ISSN 0309-0167

Aim: Reliable makers for progenitor cells in the human stomach have not been elucidated. The aim of the present study was to clarify whether Musashi-1 (Msi-1), which has recently been proposed as a stem cell marker in mouse intestine, serves as a marker for progenitor cells in human stomach. Methods and results: Immunohistochemistry revealed that Msi-1+ cells were detected especially in the isthmus/neck region (the putative position of stem cells) of the adult antrum, but were limited to the basal regions of fetal pyloric glands during the early stages of development. These results suggest that Msi-1 expression occurs specifically in the stem cell-containing regions. Msi-1+ cells were intermingled with proliferating cell nuclear antigen (PCNA)+ cells in the isthmus/neck region of the adult antrum, but did not coexpress PCNA or Ki67. Msi-1 expression overlapped partly with expression of MUC5AC and MUC6, indicating that Msi-1+ cells retain some features of both foveolar and pyloric gland cell differentiation phenotypes. In contrast, Msi-1 expression in gastric glands showing intestinal metaplasia (IM) became weaker than that in the glands without IM. Conclusion: The specific expression of Msi-1 within the proliferative regions suggests that Msi-1 is a marker of cells with progenitor characteristics before active proliferation in human antrum. © 2005 Blackwell Publishing Limited.

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Correlation between Musashi-1 and c-hairy-1 expression and cell proliferation activity in the developing intestine and stomach of both chicken and mouse

Asai Rieko, Okano Hideyuki, Yasugi Sadao

Development Growth and Differentiation 47 ( 8 ) 501 - 510 2005.10

ISSN 0012-1592

Musashi-1 (Msi-1) is an RNA-binding protein that plays key roles in the maintenance of neural stem cell states and in their differentiation into neural cells. Msi-1 has also been proposed as a candidate marker gene of mammalian intestinal stem cells and their immediate lineages. In this study, we examined Msi-1 expression in the small intestine and the stomach of both chicken and mouse during embryonic, fetal and postnatal development. In addition, we analyzed the expression of c-hairy-1, a chicken homologue of mouse Hes1, and assessed the proliferative activity of the cells expressing both of these factors. Significantly, during the development of these digestive organs in both species Msi-1 expression showed dynamic changes, suggesting that it is important for digestive organ development, particularly for epithelial differentiation. Based on our observations of the expression patterns of Msi-1 and c-hairy-1 in the adult small intestine, we speculate that Msi-1 is also a stem cell marker of the chicken small intestinal epithelium.

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Establishment of novel embryonic stem cell lines derived from the common marmoset (Callithrix jacchus)

Sasaki Erika, Hanazawa Kisaburo, Kurita Ryo, Akatsuka Akira, Yoshizaki Takahito, Ishii Hajime, Tanioka Yoshikuni, Ohnishi Yasuyuki, Suemizu Hiroshi, Sugawara Ayako, Tamaoki Norikazu, Izawa Kiyoko, Nakazaki Yukoh, Hamada Hiromi, Suemori Hirofumi, Asano Shigetaka, Nakatsuji Norio, Okano Hideyuki, Tani Kenzaburo

Stem Cells 23 ( 9 ) 1304 - 1313 2005.10

ISSN 1066-5099

The successful establishment of human embryonic stem cell (hESC) lines has inaugurated a new era in regenerative medicine by facilitating the transplantation of differentiated ESCs to specific organs. However, problems with the safety and efficacy of hESC therapy in vivo remain to be resolved. Preclinical studies using animal model systems, including nonhuman primates, are essential to evaluate the safety and efficacy of hESC therapies. Previously, we demonstrated that common marmosets are suitable laboratory animal models for preclinical studies of hematopoietic stem cell therapies. As this animal model is also applicable to preclinical trials of ESC therapies, we have established novel common marmoset ESC (CMESC) lines. To obtain marmoset embryos, we developed a new embryo collection system, in which blastocysts can be obtained every 3 weeks from each marmoset pair. The inner cell mass was isolated by immunosurgery and plated on a mouse embryonic feeder layer. Some of the CMESC lines were cultured continuously for more than 1 year. These CMESC lines showed alkaline phosphatase activity and expressed stage-specific embryonic antigen (SSEA)-S, SSEA-4, TRA-1-60, and TRA-1-81. On the other hand, SSEA-1 was notdetected. Furthermore, our novel CMESCs are pluripotent, as evidenced by in vivo teratoma formation in immunodeficient mice and in vitro differentiation experiments. Our established CMESC lines and the common marmoset provide an excellent experimental model system for understanding differentiation mechanisms, as well as the development of regenerative therapies using hESCs. ©Alpha Med Press.

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Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart

Tomita Yuichi, Matsumura Keisuke, Wakamatsu Yoshio, Matsuzaki Yumi, Shibuya Isao, Kawaguchi Haruko, Ieda Masaki, Kanakubo Sachiko, Shimazaki Takuya, Ogawa Satoshi, Osumi Noriko, Okano Hideyuki, Fukuda Keiichi

Journal of Cell Biology 170 ( 7 ) 1135 - 1146 2005.09

ISSN 0021-9525

Arodent cardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressed nestin, Musashi-1, and multidrug resistance transporter gene 1, markers of undifferentiated neural precursor cells. These markers were lost following differentiation, and were replaced by the expression of neuron-, glial-, smooth muscle cell-, or cardiomyocyte-specific proteins. Cardiosphere-derived cells transplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract and contributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells. Lineage studies using double transgenic mice encoding protein 0-Cre/Floxed-EGFP revealed undifferentiated and differentiated neural crest-derived cells in the fetal myocardium. Undifferentiated cells expressed GATA-binding protein 4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes. These results suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormant multipotent stem cells-and under the right conditions-differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and smooth muscle. © The Rockefeller University Press.

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Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia

Tonchev Anton B., Yamashima Tetsumori, Sawamoto Kazunobu, Okano Hideyuki

Journal of Neuroscience Research 81 ( 6 ) 776 - 788 2005.09

ISSN 0360-4012

Cerebral ischemia in adult rodent models increases the proliferation of endogenous neural progenitor cells residing in the subventricular zone along the anterior horn of the lateral ventricle (SVZa) and induces neurogenesis in the postischemic striatum and cortex. Whether the adult primate brain preserves a similar ability in response to an ischemic insult is uncertain. We used the DNA synthesis indicator bromodeoxyuridine (BrdU) to label newly generated cells in adult macaque monkeys and show here that the proliferation of cells with a progenitor phenotype (double positive for BrdU and the markers Musashi1, Nestin, and βIII-tubulin) in SVZa increased during the second week after a 20-min transient global brain ischemia. Subsequent progenitor migration seemed restricted to the rostral migratory stream toward the olfactory bulb and ischemia increased the proportion of adult-generated cells retaining their location in SVZa with a progenitor phenotype. Despite the lack of evidence for progenitor cell migration toward the postischemic striatum or prefrontal neocortex, a small but sustained proportion of BrdU-labeled cells expressed features of postmitotic neurons (positive for the protein NeuN and the transcription factors Tbr1 and Islet1) in these two regions for at least 79 days after ischemia. Taken together, our data suggest an enhanced neurogenic response in the adult primate telencephalon after a cerebral ischemic insult. © 2005 Wiley-Liss, Inc.

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Inhibition of glioma cell proliferation by neural stem cell factor

Suzuki Tsuyoshi, Izumoto Shuichi, Wada Kouichi, Fujimoto Yasunori, Maruno Motohiko, Yamasaki Mami, Kanemura Yonehiro, Shimazaki Takuya, Okano Hideyuki, Yoshimine Toshiki

Journal of Neuro-Oncology 74 ( 3 ) 233 - 239 2005.09

ISSN 0167-594X

Neural stem cells (NSC) have unique differentiation-, proliferation-, and motility properties. To investigate whether they secrete factors that interfere with the proliferation of glioma cells, we grew glioma cells in conditioned medium (CM) obtained from cultures of neurospheres including neural stem/progenitor cells (NSPC) isolated from embryonic (E14)- or adult mouse brain or fetal human brain. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and BrdU-labeling assays showed that CM from NSPC (NSPC/CM) contained factor(s) that inhibited the proliferation of glioma cells by 28-87%. Filter-fractionation of NSPC/CM revealed that the 50,000-100,000 nominal molecular weight limit (NMWL) fraction contained the inhibitory activity. On the basis of these observations we transplanted 203G glioma cells and/or NSPC into the intrathecal space of the cisterna magna of mice to investigate whether NSPC interfere with the proliferation of glioma cells in vivo. Mice transplanted with both 203G and NSPC survived significantly longer than did mice transplanted only with 203G. We concluded that NSPC secrete factor(s) that may control glioma cell proliferation. © Springer 2005.

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Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury

Tamura Mutsuhiro, Nakamura Masaya, Ogawa Yuto, Toyama Yoshiaki, Miura Masayuki, Okano Hideyuki

GLIA 51 ( 4 ) 312 - 321 2005.09

ISSN 0894-1491

Functional impairment after spinal cord injury (SCI) is attributed to neuronal cell necrosis death and axonotmesis, with further worsening caused by the accompanying apoptosis of myelin-forming oligodendrocytes (OLGs). However, it is unclear as to how much OLG apoptosis contributes to functional impairment. To address this issue, we used transgenic mice characterized by the targeted expression of p35, a broad-spectrum caspase inhibitor, in OLGs using the cre/loxP system (referred to as cre/p35 transgenic mice). In this study, we examined the motor function and histopathologic changes after a contusive thoracic spinal cord injury in the cre/p35 transgenic mice. A larger number of OLGs and a lesser extent of demyelination were observed after SCI in the cre/p35 transgenic mice than in the control cre mice, which did not carry the p35 transgene. Furthermore, the motor function of the hindlimbs recovered to a significantly better degree in the cre/p35 transgenic mice than in the control ere mice. Thus, the inhibition of OLG apoptosis decreased the extent of functional impairment after SCI. These findings suggest that the inhibition of OLG apoptosis may be a potential treatment for SCI. ©2005 Wiley-Liss, Inc.

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