Details of a Researcher - Okano, Hideyuki

Papers - Okano, Hideyuki

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Transplantation of embryonic spinal cord-derived neurospheres support growth of supraspinal projections and functional recovery after spinal cord injury in the neonatal rat

Nakamura M., Okano H., Toyama Y., Dai H. N., Finn T. P., Bregman Barbara S.

Journal of Neuroscience Research 81 ( 4 ) 457 - 468 2005.08

ISSN 0360-4012

Great interest exists in using cell replacement strategies to repair the damaged central nervous system. Previous studies have shown that grafting rat fetal spinal cord into neonate or adult animals after spinal cord injury leads to improved anatomic growth/plasticity and functional recovery. It is clear that fetal tissue transplants serve as a scaffold for host axon growth. In addition, embryonic Day 14 (E14) spinal cord tissue transplants are also a rich source of neural-restricted and glial-restricted progenitors. To evaluate the potential of E14 spinal cord progenitor cells, we used in vitro-expanded neurospheres derived from embryonic rat spinal cord and showed that these cells grafted into lesioned neonatal rat spinal cord can survive, migrate, and differentiate into neurons and oligodendrocytes, but rarely into astrocytes. Synapses and partially myelinated axons were detected within the transplant lesion area. Transplanted progenitor cells resulted in increased plasticity or regeneration of corticospinal and brainstem-spinal fibers as determined by anterograde and retrograde labeling. Furthermore, transplantation of these cells promoted functional recovery of locomotion and reflex responses. These data demonstrate that progenitor cells when transplanted into neonates can function in a similar capacity as transplants of solid fetal spinal cord tissue. © 2005 Wiley-Liss, Inc.

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Comparison of various bone marrow fractions in the ability to participate in vascular remodeling after mechanical injury

Sahara Makoto, Sata Masataka, Matsuzaki Yumi, Tanaka Kimie, Morita Toshihiro, Hirata Yasunobu, Okano Hideyuki, Nagai Ryozo

Stem Cells 23 ( 7 ) 874 - 878 2005.08

ISSN 1066-5099

In contrast to conventional assumption, recent reports propose the possibility that hematopoietic stem cells (HSCs) may have broader potential to differentiate into various cell types. Here, we tested the pluripotency of HSCs by comparing vascular lesions induced by mechanical injury after bone marrow reconstitution with total bone marrow (TBM) cells, C-KH⁺ Sca-1 ⁺ Lin- (KSL) cells, or a single HSC cell (Tip-SP CD34-KSL cell, CD34- c-Kit⁺ Sca-1⁺ Lin- cell with the strongest dyeefflux activity) harboring green fluorescent protein (GFP). The lesions contained a significant number of GFP-positive cells in the TBM and KSL groups, whereas GFP-positive cells were rarely detected in the HSC group. These results suggest that transdifferentiation of a highly purified HSC seems to be a rare event, if it occurs at all, whereas bone marrow cells including the KSL fraction can give rise to vascular cells that substantially contribute to repair or lesion formation after mechanical injury. ©AlphaMed Press.

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Inflammation and regeneration of injured spinal cord: effects of the stem cell transplantation and blockade of IL-6 signaling

Okano, Hideyuki, Okada, Seiji, Nakamura, Masaya, Toyama, Yoshiaki

INFLAMMATION RESEARCH 54 S92 - S92 2005.08

Research paper (scientific journal), ISSN 1023-3830

Increased number of neural progenitors in human temporal lobe epilepsy

Crespel Arielle, Rigau Valérie, Coubes Philippe, Rousset Marie Claude, De Bock Frédéric, Okano Hideyuki, Baldy-Moulinier Michel, Bockaert Joël, Lerner-Natoli Mireille

Neurobiology of Disease 19 ( 3 ) 436 - 450 2005.08

ISSN 0969-9961

An increased neurogenesis is reported in animal models of mesial temporal lobe epilepsy (MTLE) but the fate of newborn cells is unknown. Here, we attempted to demonstrate neurogenesis in adult epileptic tissue obtained after hippocampectomy. MTLE hippocampi showed increased expression of division markers and of Musashi-1, a marker of neural progenitors, compared to control hippocampi. Large quantities of Musashi-1⁺ cells were obvious in the subgranular layer and the subventricular zone, both known neurogenic areas, and in the fissura hippocampi. Musashi-1 was expressed by small cells that were mainly vimentin⁺ or nestin⁺, rarely Dcx⁺ or PSA-NCAM⁺ and negative for markers of mature neurons or astrocytes. Some of them are present in the granular layer, the hilus, and CA1 area resembling the ectopic positions described in rodents. These findings demonstrate that neural progenitors proliferate in chronic epilepsy and suggest that the fissura hippocampi behaves like another neurogenic area. © 2005 Elsevier Inc. All rights reserved.

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Characterization of ABC transporter ABCB1 expressed in human neural stem/progenitor cells

Islam Mohammed Omedul, Kanemura Yonehiro, Tajria Jesmin, Mori Hideki, Kobayashi Satoshi, Shofuda Tomoko, Miyake Jun, Hara Masayuki, Yamasaki Mami, Okano Hideyuki

FEBS Letters 579 ( 17 ) 3473 - 3480 2005.07

ISSN 0014-5793

We investigated the localization and functional expression of the ABC transporter ABCB1 in human fetal neural stem/progenitor cells (hNSPCs). RT-PCR analysis revealed ABCB1 gene expression in hNSPCs. We found a single band in immunoblotted hNSPCs lysates probed with ABCB1 antibody, and detected ABCB1 at the hNSPCs cell membrane by immunocytochemistry and subcellular fractionation. ABCB1 inhibitors and substrate, and ATP-depleting agents enhanced hNSPCs' rhodamine 123 accumulation, and hNSPCs microsomes had vanadate-sensitive ATPase activity. ABCB1 and nestin expression decreased during hNSPCs differentiation, while the astroglial marker GFAP increased. ABCB1 may maintain hNSPCs in an undifferentiated state and could be a neural stem/progenitor marker. © 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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Use of TH-EGFP transgenic mice as a source of identified dopaminergic neurons for physiological studies in postnatal cell culture

Jomphe C., Bourque M. J., Fortin G. D., St-Gelais F., Okano H., Kobayashi K., Trudeau L. E.

Journal of Neuroscience Methods 146 ( 1 ) 1 - 12 2005.07

ISSN 0165-0270

The physiological and pharmacological properties of dopaminergic neurons in the brain are of major interest. Although much has been learned from cell culture studies, the physiological properties of these neurons remain difficult to study in such models because they are usually in minority and are difficult to distinguish from other non-dopaminergic neurons. Here we have taken advantage of a recently engineered transgenic mouse model expressing enhanced green fluorescence protein (EGFP) under the control of the tyrosine hydroxylase promoter to establish a more effective dopaminergic neuron cell culture model. We first evaluated the specificity of the EGFP expression. Although ectopic expression of EGFP was found in cultures derived from postnatal day 0 pups, this decreased over time in culture such that after 2 weeks, approximately 70% of EGFP-expressing neurons were dopaminergic. We next sought to validate this dopaminergic neuron culture model. We evaluated whether EGFP-expressing dopaminergic neurons displayed some of the well-established properties of dopaminergic neurons. Autoreceptor stimulation inhibited the activity of dopaminergic neurons while neurotensin receptor activation produced the opposite effect. Confocal imaging of the synaptic vesicle optical tracer FM4-64 in EGFP-expressing dopaminergic neurons demonstrated the feasibility of high resolution monitoring of the activity of single terminals established by these neurons. Together, this work provides evidence that primary cultures of postnatal TH-EGFP mice currently represent an excellent model to study the properties of these cells in culture. © 2005 Elsevier B.V. All rights reserved.

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Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice

Yamashita Toru, Sawamoto Kazunobu, Suzuki Shigeaki, Suzuki Norihiro, Adachi Kazuhide, Kawase Takeshi, Mihara Masahiko, Ohsugi Yoshiyuki, Abet Koji, Okano Hideyuki

Journal of Neurochemistry 94 ( 2 ) 459 - 468 2005.07

ISSN 0022-3042

Interleukin (IL)-6 expression transiently increases in the acute phase of cerebral ischemia. To investigate the physiological significance of endogenous IL-6 expression and to identify the main signal pathway for the action of IL-6, we administered anti-mouse IL-6 receptor monoclonal antibody (IL-6RA), which blocks IL-6 signaling, to mice immediately after a 45-min period of middle cerebral artery occlusion (MCAO). At 6 h after MCAO, IL-6RA administration had resulted in a significant reduction in the amount of phosphorylated signal transducer and activator of transcription-3 (Stat3) protein in the peri-infarct area of the cortex. At 24 h after MCAO, blockade of IL-6 signaling had led to an increase in number of apoptotic cells in the peri-infarct area and enlargement of the size of the infarct, and it had adversely affected neurological function. These results suggest that endogenous IL-6 plays a critical role in preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia and that its role may be mediated by Stat3 activation. © 2005 International Society for Neurochemistry.

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Possibility for neurogenesis in substantia nigra of parkinsonian brain

Yoshimi Kenji, Ren Yong Ri, Seki Tatsunori, Yamada Masanori, Ooizumi Hideki, Onodera Masafumi, Saito Yuko, Murayama Shigeo, Okano Hideyuki, Mizuno Yoshikuni, Mochizuki Hideki

Annals of Neurology 58 ( 1 ) 31 - 40 2005.07

ISSN 0364-5134

Recent studies of enhanced hippocampal neurogenesis by antidepressants suggest enhancement of neurogenesis is a potentially effective therapy in neurodegenerative diseases. In this study, we evaluated nigral neurogenesis in animals and autopsy brains including patients with Parkinson's disease (PD). First, proliferating cells in substantia nigra were labeled with retroviral transduction of green fluorescent protein, which is an efficient method to label neuronal stem cells. Subsequent differentiation of labeled cells was followed; many transduced cells became microglia, but no differentiation into tyrosine hydroxylase-positive neurons was detected at 4 weeks after injection, in both intact rodents and those treated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. Second, polysialic acid (PSA)-like immunoreactivity, indicative of newly differentiated neurons, was detected in the substantia nigra of rodent, primate, and human midbrains. A large number of PSA-positive cells were detected in the substantia nigra pars reticulata of some patients with PD. In rats and a macaque monkey, the dopamine-depleted hemispheres showed more PSA staining than the intact side. A small number of tyrosine hydroxylase-positive cells were PSA-positive. Our results suggest enhanced neural reconstruction in PD, which may be important in the design of new therapies against the progression of PD. © 2005 American Neurological Association.

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Potential functional neural repair with grafted neural stem cells of early embryonic neuroepithelial origin

Uchida Koichi, Momiyama Toshihiko, Okano Hideyuki, Yuzaki Michisuke, Koizumi Amane, Mine Yutaka, Kawase Takeshi

Neuroscience Research 52 ( 3 ) 276 - 286 2005.07

ISSN 0168-0102

The fate of grafted neuroepithelial stem cells in the normal mature brain environment was assessed both morphologically and electrophysiologically to confirm their feasibility in the functional repair of damaged neural circuitry. The neuroepithelial stem cells were harvested from the mesencephalic neural plate of transgenic green fluorescence protein-carrying rat embryos, and implanted into the normal adult rat striatum. The short- and long-term differentiation pattern of donor-derived cells was precisely monitored immunohistochemically. The functional abilities of the donor-derived cells and communication between them and the host were investigated using host-rat brain slices incorporating the graft with whole-cell patch-clamp recording. Vigorous differentiation of the neuroepithelial stem cells into mostly neurons was noted in the short-term with positive staining for tyrosine hydroxylase, suggesting that the donor-derived cells were exclusively following their genetically programmed fate, together with gamma-aminobutyric acid (GABA) and glutamate expression. In the long-term, the large number of donor-derived neurons was sustained, but the staining pattern showed expression of dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein 32, suggesting that some neurons were following environmental cues, together with the appearance of some cholinergic neurons. Some donor-derived astrocytes were also seen in the graft. Many action potentials indicating the presence of both dopaminergic and non-dopaminergic patterns could be elicited and recorded in the donor-derived neurons in addition to spontaneous glutamatergic and GABAergic post-synaptic currents which were strongly shown to be of host origin. Neuroepithelial stem cells are therefore an attractive candidate as a source of donor material for intracerebral grafting in functional repair. © 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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Function of RNA-binding protein Musashi-1 in stem cells

Okano Hideyuki, Kawahara Hironori, Toriya Masako, Nakao Keio, Shibata Shinsuke, Imai Takao

Experimental Cell Research 306 ( 2 ) 349 - 356 2005.06

ISSN 0014-4827

Musashi is an evolutionarily conserved family of RNA-binding proteins that is preferentially expressed in the nervous system. The first member of the Musashi family was identified in Drosophila. This protein plays an essential role in regulating the asymmetric cell division of ectodermal precursor cells known as sensory organ precursor cells through the translational regulation of target mRNA. In the CNS of Drosophila larvae, however, Musashi is expressed in proliferating neuroblasts and likely has a different function. Its probable mammalian homologue, Musashi-1, is a neural RNA-binding protein that is strongly expressed in fetal and adult neural stem cells (NSCs). Mammalian Musashi-1 augments Notch signaling through the translational repression of its target mRNA, m-Numb, thereby contributing to the self-renewal of NSCs. In addition to its functions in NSCs, the role of mammalian Musashi-1 protein in epithelial stem cells, including intestinal and mammary gland stem cells, is attracting increasing interest. © 2005 Elsevier Inc. All rights reserved.

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Musculin/MyoR is expressed in kidney side population cells and can regulate their function

Hishikawa Keiichi, Marumo Takeshi, Miura Shigeki, Nakanishi Asato, Matsuzaki Yumi, Shibata Katsunori, Ichiyanagi Tomoko, Kohike Hiroko, Komori Takuya, Takahashi Ichiro, Takase Osamu, Imai Naohiko, Yoshikawa Masahiro, Inowa Toshihiko, Hayashi Matsuhiko, Nakaki Toshio, Nakauchi Hiromitsu, Okano Hideyuki, Fujita Toshiro

Journal of Cell Biology 169 ( 6 ) 921 - 928 2005.06

ISSN 0021-9525

Musculin/MyoR is a new member of basic helixloop-helix transcription factors, and its expression is limited to skeletal muscle precursors. Here, we report that musculin/MyoR is expressed in adult kidney side population (SP) cells and can regulate their function. SP phenotype can be used to purify stem cell-rich fractions. Microarray analysis clarified that musculin/MyoR was exclusively expressed in kidney SP cells, and the cells resided in the renal interstitial space. Musculin/MyoR-positive cells were decreased in acute renal failure, but infusion of kidney SP cells increased musculin/MyoR-positive cells and improved renal function. Kidney SP cells in reversible acute renal failure expressed a high level of renoprotective factors and leukemia inhibitory factor (LIF), but not in irreversible chronic renal failure. In cultured kidney SP cells, LIF stimulated gene expression of renoprotective factors, and down-regulation of musculin/MyoR augmented LIF-induced gene expression. Our results suggest that musculin/MyoR may play important roles not only in developmental processes but also in regenerative processes in adult tissue. © The Rockefeller University Press.

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Drosophila deltex mediates suppressor of hairless-independent and late-endosomal activation of notch signaling

Hori, Kazuya, Ito, Mikiko, Fuwa, Takashi J., Go, Masahiro J., Okano, Hideyuki, Matsuno, Kenji

CELL STRUCTURE AND FUNCTION 30 68 - 68 2005.06

Research paper (scientific journal), ISSN 0386-7196

Role of autophagy in protein quality control in the central nervous system

Hara, Taichi, Nakamura, Kenji, Nakahara, Yohko, Migishima, Rika, Yokoyama, Minesuke, Matsui, Makoto, Okano, Hideyuki, Mizushima, Noboru

CELL STRUCTURE AND FUNCTION 30 49 - 49 2005.06

Research paper (scientific journal), ISSN 0386-7196

Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine

Matsumoto Tomoko, Okamoto Ryuichi, Yajima Tomoharu, Mori Takehiko, Okamoto Shinichiro, Ikeda Yasuo, Mukai Makio, Yamazaki Motomi, Oshima Shigeru, Tsuchiya Kiichiro, Nakamura Tetsuya, Kanai Takanori, Okano Hideyuki, Inazawa Johji, Hibi Toshifumi, Watanabe Mamoru

Gastroenterology 128 ( 7 ) 1851 - 1867 2005.06

ISSN 0016-5085

Background & Aims: We have previously reported that bone marrow (BM)-derived cells contribute to the regeneration of the human intestinal epithelium. To analyze further how these cells arise, proliferate, and differentiate as epithelial cells, histologic analysis was conducted using endoscopic specimens. Methods: Thirty biopsy specimens from 14 female, sex-mismatched BM-transplantation recipients were examined. BM-derived cells were identified by fluorescent in situ hybridization (FISH) for the Y chromosome and immunohistochemistry. Multicolor FISH was used to exclude cell fusion. These cells were further analyzed for various differentiation or proliferation markers. Results: No evidence of cell fusion was detected. BM-derived cells did not distribute within the crypt as stem cells and rarely expressed Musashi-1. However, BM-derived epithelial cells frequently expressed Ki-67, and some of these cells appeared as pairs of adjacent cells. These cells also expressed markers of all 4 lineages of terminally differentiated cells. During regeneration following graft-vs-host disease, the number of BM-derived cells was substantially increased within Ki-67-positive cells. Interestingly, the number of cells expressing markers for secretory lineage cells was significantly increased within BM-derived cells. This change was unique for BM-derived cells, resulting in a significantly increased proportion of BM-derived cells among secretory lineage cells. Conclusions: BM-derived epithelial cells arise via a mechanism other than cell fusion and rarely give rise to stem cells. However, a small proportion of these cells express proliferation markers, and a majority reside as terminally differentiated cells. During regeneration BM-derived cells increase as secretory lineage cells, thereby contributing to restore epithelial functions. © 2005 by the American Gastroenterological Association.

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Notch signaling functions as a binary switch for the determination of glandular and luminal fates of endodermal epithelium during chicken stomach development

Matsuda Yoshimasa, Wakamatsu Yoshio, Kohyama Jun, Okano Hideyuki, Fukuda Kimiko, Yasugi Sadao

Development 132 ( 12 ) 2783 - 2793 2005.06

ISSN 0950-1991

During development of the chicken proventriculus (glandular stomach), gut endoderm differentiates into glandular and luminal epithelium. We found that Delta1-expressing cells, undifferentiated cells and Notch-activated cells colocalize within the endodermal epithelium during early gland formation. Inhibition of Notch signaling using Numb or dominant-negative form of Su(H) resulted in a luminal differentiation, while forced activation of Notch signaling promoted the specification of immature glandular cells, but prevented the subsequent differentiation and the imagination of the glands. These results suggest that Delta1-mediated Notch signaling among endodermal cells functions as a binary switch for determination of glandular and luminal fates, and regulates patterned differentiation of glands in the chicken proventriculus.

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Role of IL-6 in spinal cord injury in a mouse model

Nakamura Masaya, Okada Seiji, Toyama Yoshiaki, Okano Hideyuki

Clinical Reviews in Allergy and Immunology 28 ( 3 ) 197 - 203 2005.06

ISSN 1080-0549

In recent years, various studies have been conducted toward the goal of achieving regeneration of the central nervous system using neural stem cells. However, various complex factors are involved in the regulation of neural stem cell differentiation, and many unresolved questions remain. It has been reported that after spinal cord injury, the intrinsic neural stem cells do not differentiate into neurons but, rather, into astrocytes, resulting in the formation of glial scars. Based on reports that the expression of interleukin (IL)-6 and the IL-6 receptor (IL-6R) is sharply increased in the acute stages after spinal cord injury and that IL-6 may serve as a factor strongly inducing the differentiation of neural stem cells into astrocytes, we examined the effects of an antibody to IL-6R in cases of spinal cord injury and found that the antibody suppressed secondary injury (caused by inflammatory reactions) and glial scar formation, facilitating functional recovery. This article presents the data from this investigation and discusses the relationship between IL-6 signals and spinal cord injury. © Copyright 2005 by Humana Press Inc.

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Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats

Suzuki Shigeaki, Yamashita Toru, Tanaka Kortaro, Hattori Hidenori, Sawamoto Kazunobu, Okano Hideyuki, Suzuki Norihiro

Journal of Cerebral Blood Flow and Metabolism 25 ( 6 ) 685 - 693 2005.06

ISSN 0271-678X

Cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 is known to exert a neurotrophic action in the central nervous system, although the role of this signaling in cerebral ischemia remains unknown. We examined the effect of intracerebral injection of LIF after focal cerebral ischemia in rats. The animals underwent a sham operation (sham group) or middle cerebral artery occlusion (MCAO) followed by direct injection of either vehicle (phosphate-buffered saline, the PBS group) or recombinant LIF (10 ng in the low-LIF group and 100 ng in the high-LIF group) into the cerebral cortex adjacent to the inner boundary zone of the infarct area, and neurologic and histologic evaluations were conducted 24 h later. Expression of LIFR, gp130, and phosphorylated Stat3, Akt, and ERK1/2 was investigated by Western blot analysis and immunohistochemistry. The neurologic deficits and ischemic damage were significantly less severe in the high-LIF group than in the PBS group and the low-LIF group. Leukemia inhibitory factor receptor and gp130 were expressed in neurons, and the ischemic damage of these proteins was rescued in the high-LIF group. Early induction of phosphorylated Stat3 was significantly detected on the ischemic side in the high-LIF group after LIF injection. Exogenous LIF attenuates ischemic brain injury by activating cytokine signaling through LIFR/gp130. © 2005 ISCBFM All rights reserved.

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Prospective characterization of neural stem cells by flow cytometry analysis using a combination of surface markers

Nagato Masako, Heike Toshio, Kato Takeo, Yamanaka Yasunari, Yoshimoto Momoko, Shimazaki Takuya, Okano Hideyuki, Nakahata Tatsutoshi

Journal of Neuroscience Research 80 ( 4 ) 456 - 466 2005.05

ISSN 0360-4012

Neural stem cells (NSCs) with self-renewal and multilineage differentiation properties can potentially repair degenerating or damaged neural tissue. Here, we have enriched NSCs from neurospheres, which make up a heterogeneous population, by fluorescence-activated cell sorting (FACS) with antibodies against syndecan-1, Notch-1, and integrin-β1, which were chosen as candidates for hematopoietic cell-or somatic stem cell-markers. Antigen-positive cells readily initiated neurosphere formation, but cells lacking these markers did so less readily. Doubly positive cells expressing both syndecan-1 and Notch-1 underwent neurosphere formation more efficiently than did singly positive cells. The progeny of sorted cells could differentiate into neurons and glial cells both in vitro and in vivo. These antibodies were also useful for isolating cells from the murine embryonic day 14.5 brain that efficiently formed neurospheres. In contrast, there was no distinct difference in neurosphere formation efficiency between Hoechst 33342-stained side population cells and main population cells, although the former are known to have a stem cell phenotype in various tissues. These results indicate the usefulness of syndecan-1, Notch-1, and integrin-β1 as NSC markers. © 2005 Wiley-Liss, Inc.

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Functional expression of ABCG2 transporter in human neural stem/progenitor cells

Islam Mohammed Omedul, Kanemura Yonehiro, Tajria Jesmin, Mori Hideki, Kobayashi Satoshi, Hara Masayuki, Yamasaki Mami, Okano Hideyuki, Miyake Jun

Neuroscience Research 52 ( 1 ) 75 - 82 2005.05

ISSN 0168-0102

We have studied the expression, localization, and function of the ABCG2 transporter, a universal stem cell marker, at the protein level in human cultured neural stem/progenitor cells (hNSPCs) using immunoblotting, immunofluorescence, and ATPase assays. Human NSPCs were isolated from human fetal brain and propagated in vitro as neurospheres. Both the cells in neurospheres and single cells dissociated from neurospheres showed high levels of ABCG2, and about 63% of the cells in neurospheres were ABCG2-positive, similar to the proportion of nestin-positive cells, and in most cases the ABCG2 and nestin staining co-localized in the same cells. Both the three-dimensional structure of single hNSPCs stained with anti-ABCG2 antibodies and an examination using a biochemical marker for the plasma membrane indicated that ABCG2 was localized to the plasma membrane of hNSPCs. The ABCG2 expressed in hNSPCs had prazosin-sensitive ATP hydrolysis activity, and the ABCG2 level was sharply down-regulated during hNSPC differentiation. All these results suggested that ABCG2, was functionally expressed in hNSPCs. ABCG2 might play a significant role in maintaining human neural stem cells in an undifferentiated state and in protecting hNSPCs from xenobiotics or other toxic substances in vivo. © 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

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Transplantation of human neural stem cells for spinal cord injury in primates

Iwanami A., Kaneko S., Nakamura M., Kanemura Y., Mori H., Kobayashi S., Yamasaki M., Momoshima S., Ishii H., Ando K., Tanioka Y., Tamaoki N., Nomura T., Toyama Y., Okano Hideyuki

Journal of Neuroscience Research 80 ( 2 ) 182 - 190 2005.04

ISSN 0360-4012

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI. © 2005 Wiley-Liss, Inc.

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