Details of a Researcher - Nakamura, Masaya

Papers - Nakamura, Masaya

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Plasma as a scaffold for regeneration of neural precursor cells after transplantation into rats with spinal cord injury

Takenaga Mitsuko, Ohta Yuki, Tokura Yukie, Hamaguchi Akemi, Suzuki Noboru, Nakamura Masaya, Okano Hideyuki, Igarashi Rie

Cell Transplantation 16 ( 1 ) 57 - 65 2007

ISSN 0963-6897

The present study investigated whether plasma could be useful as a scaffold for cell transplantation in rats with spinal cord injury (SCI). Transplantation of cells with plasma promoted the recovery of SCI-induced motor dysfunction. Immunohistochemical analysis revealed that the grafted cells had differentiated into the neural lineage. When dissociated neural precursor cells were cultured with plasma, extensive neurite outgrowth was observed along with increased expression of p35 and NF68. Neural markers were also expressed by the cultured cells. Culture with plasma reduced thymidine incorporation, but promoted cell growth and increased the RNA contents. These findings suggest that the cells underwent differentiation into neurons in the presence of plasma. In conclusion, plasma could be a promising scaffold for cell transplantation therapy. Copyright © 2007 Cognizant Comm. Corp.

Establishment of three-dimensional culture of neural stem/progenitor cells in collagen Type-1 Gel

Watanabe Kota, Nakamura Masaya, Okano Hideyuki, Toyama Yoshiaki

Restorative Neurology and Neuroscience 25 ( 2 ) 109 - 117 2007

ISSN 0922-6028

Purpose: Recent studies demonstrated that transplanting neural stem/precursor cells (NSPCs) into an injured spinal cord of adult rat promotes functional recovery. The functional recovery from spinal cord injury might be enhanced by transplanting NSPCs with a scaffold that fills the cavity, entraps the NSPCs in the cavity, and acts as an attachment for neurite extension. We recently focused on collagen type-1 as a scaffold for NSPC transplantation into the injured spinal cord. In the present study, we determined the optimal conditions for culturing NSPCs in 3D collagen type-1 gel with respect to cell survival and cell migration. We, then, evaluated the ability of NSPCs to differentiate under the optimal condition. Methods: NSPCs were derived from the striatum of rat embryos. To determine the optimal cell density and collagen concentration for 3D collagen gel culture for NSPC, we performed viability assay and migration assay. Then, we examined the proportion of phenotypes differentiated from NSPC in that optimal condition. Results: In viability assay, the viability rate increased as the NSPC density increased, and peaked at 1 × 10⁷ to 5 × 10⁷ cell/ml. For collagen concentration, the viability rate increased as the collagen concentration decreased. In migration assay, cell migration was most extensive at collagen concentrations between 0.3 and 0.75 mg/ml. Migration distances gradually declined as collagen concentrations increased. In the optimal condition, NSPCs differentiated into neurons (40.1%), astrocytes (53.1%), and oligodendrocytes (5.3%) in 3D collagen gel culture. Conclusion: The optimal conditions for NSPC culture in 3D collagen gel was a cell density between 1 × 10⁷ and 5 × 10⁷ cells/ml and a collagen concentration between 0.5 and 0.75 mg/ml. Under the condition, NSPCs could differentiate into neurons, astrocytes, and oligodendrocytes. © 2007 - IOS Press and the authors. All rights reserved.

Surgical outcomes of spinal cord astrocytomas

Nakamura M., Chiba K., Ishii K., Ogawa Y., Takaishi H., Matsumoto M., Toyama Y.

Spinal Cord 44 ( 12 ) 740 - 745 2006.12

ISSN 1362-4393

Study design:Retrospective case series.Objectives:To analyze prognostic factors for patients with spinal cord astrocytomas.Setting:Department of Orthopaedic Surgery, Keio University, Japan.Methods:Seven patients received total excisions (group T), eight underwent partial excisions (group P), and 15 had excisional biopsies (group B). Impacts of the tumor histological grade, the level of the tumor, the types of surgical interventions, and the use of adjuvant radiotherapies on the survival and functional outcomes of 30 patients (18 in low-grade and 12 high-grade malignancy tumors) were analyzed.Results:The survival rate of the low-grade malignancy group was significantly higher than that of the high-grade group. The survival rate of the patients with thoracic astrocytomas was significantly higher than those with cervical astrocytomas. In both the low- and high-grade groups, the survival rates in groups P/T were significantly higher than those in group B. In the low-grade group, five patients, whose preoperative functional statuses were classified as 'fair' or better, remained 'fair' or better after surgery. In the high-grade group, the postoperative functional statuses were classified as 'no change' or 'aggravated' in all except two patients. No significant difference in the survival rates was detected between patients with and without adjuvant radiotherapy.Conclusions: The tumor grade and the extent of tumor resection were significant prognostic factors for survival rate. In low-grade malignancy group, good motor function was retained when surgeries were performed before substantial neurological deterioration. The efficacy of postoperative radiotherapy has yet to be determined and needs further study. © 2006 International Spinal Cord Society All rights reserved.

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Long-term results of expansive open-door laminoplasty for cervical myelopathy - Average 14-year follow-up study

Chiba Kazuhiro, Ogawa Yuto, Ishii Ken, Takaishi Hironari, Nakamura Masaya, Maruiwa Hirofumi, Matsumoto Morio, Toyama Yoshiaki

Spine 31 ( 26 ) 2998 - 3005 2006.12

ISSN 0362-2436

STUDY DESIGN. Retrospective case series on long-term follow-up results of original expansive open-door laminoplasty for cervical myelopathy due to cervical spondylosis (CSM) and ossification of posterior longitudinal ligament (OPLL). OBJECTIVES. To elucidate efficacy and problems of original open-door laminoplasty to improve future surgical outcomes. SUMMARY OF BACKGROUND DATA. Little information is available on long-term outcomes of original open-door laminoplasty without grafts, implants, or instruments. METHOD. The study group included 80 patients who underwent original open-door laminoplasty and were followed for minimum 10 years. Clinical results, including Japanese Orthopedic Association scores, recovery rates, occurrences of complications, and long-term deterioration were investigated. Cervical alignments, type of OPLL, cervical range of motion, anteroposterior diameter of spinal canal, and progression of OPLL were assessed on plain radiographs. Spinal cord decompression was verified on magnetic resonance imaging. RESULTS. Average Japanese Orthopedic Association score and recovery rate improved significantly until 3 years after surgery and remained at an acceptable level in both cervical spondylosis and OPLL patients with slight deterioration after 5 years. Segmental motor palsy developed in 8 patients. Late deterioration, mainly lower extremity motor score decline, developed in 8 CSM and 16 OPLL patients. Overall cervical range of motion decreased by 36%. Patients with cervical lordosis decreased gradually in both patient groups. Such changes in alignments did not affect surgical results in CSM patients, while OPLL patients with preoperative kyphosis had lower recovery rates than those with straight and lordotic alignments. OPLL progression that was detected in 66% of patients did not affect clinical results. Although infrequent, magnetic resonance imaging revealed atrophy of spinal cord, spinal cord compression at adjacent segments due to degenerative changes and OPLL progression. CONCLUSIONS. Long-term results of open-door laminoplasty without bone graft, graft substitutes, or instruments were satisfactory. However, segmental motor paralysis, kyphosis, established before and after surgery, OPLL progression, and late deterioration due to age-related degeneration remain challenging problems. © 2006 Lippincott Williams & Wilkins, Inc.

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A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord

Kaneko Shinjiro, Iwanami Akio, Nakamura Masaya, Kishino Akiyoshi, Kikuchi Kaoru, Shibata Shinsuke, Okano Hirotaka J., Ikegami Takeshi, Moriya Ayako, Konishi Osamu, Nakayama Chikao, Kumagai Kazuo, Kimura Toru, Sato Yasufumi, Goshima Yoshio, Taniguchi Masahiko, Ito Mamoru, He Zhigang, Toyama Yoshiaki, Okano Hideyuki

Nature Medicine 12 ( 12 ) 1380 - 1389 2006.12

ISSN 1078-8956

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI. © 2006 Nature Publishing Group.

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Neutralization of ciliary neurotrophic factor reduces astrocyte production from transplanted neural stem cells and promotes regeneration of corticospinal tract fibers in spinal cord injury

Ishii Ken, Nakamura Masaya, Dai HaiNing, Finn Tom P., Okano Hideyuki, Toyama Yoshiaki, Bregman Barbara S.

Journal of Neuroscience Research 84 ( 8 ) 1669 - 1681 2006.12

ISSN 0360-4012

Transplantation of neural stem cells (NSC) into lesioned spinal cord offers the potential to increase regeneration by replacing lost neurons or oligodendrocytes. The majority of transplanted NSC, however, typically differentiate into astrocytes that may exacerbate glial scar formation. Here we show that blocking of ciliary neurotrophic factor (CNTF) with anti-CNTF antibodies after NSC transplant into spinal cord injury (SCI) resulted in a reduction of glial scar formation by 8 weeks. Treated animals had a wider distribution of transplanted NSC compared with the control animals. The NSC around the lesion coexpressed either nestin or markers for neurons, oligodendrocytes, or astrocytes. Approximately 20% fewer glial fibrillary acidic protein-positive/bromodeoxyuridine (BrdU)-positive cells were seen at 2, 4, and 8 weeks postgrafting, compared with the control animals. Furthermore, more CNPase⁺/BrdU⁺ cells were detected in the treated group at 4 and 8 weeks. These CNPase⁺ or Rip⁺ mature oligodendrocytes were seen in close proximity to host corticospinal tract (CST) and 5HT⁺ serotonergic axon. We also demonstrate that the number of regenerated CST fibers both at the lesion and at caudal sites in treated animals was significantly greater than that in the control animals at 8 weeks. We suggest that the blocking of CNTF at the beginning of SCI provides a more favorable environment for the differentiation of transplanted NSC and the regeneration of host axons. © 2006 Wiley-Liss, Inc.

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Postoperative factors affecting neurological recovery after surgery for cervical spondylotic myelopathy

Ogawa Yuto, Chiba Kazuhiro, Matsumoto Morio, Nakamura Masaya, Takaishi Hironari, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 ( 6 ) 483 - 487 2006.12

ISSN 1547-5654

Object. Many prognostic factors associated with surgery for cervical spondylotic myelopathy (CSM) have been detailed in the literature. All of these factors, however, are defined preoperatively. If it is possible to clarify factors influencing surgical results that can be modulated after surgery, then the overall results of surgery may improve. The purpose of this study was to elucidate such postoperative factors affecting neurological recovery. Methods. The authors assessed the surgical outcomes obtained in 183 patients with CSM who underwent expansive open-door laminoplasty between 1993 and 2004 and who underwent follow up for a minimum of 1 year. They classified the cases into two groups according to the degree of neurological recovery: an excellent recovery group, comprising patients in whom the recovery rates were greater than 75%, and a poor recovery group, composed of patients in whom the recovery rates were lower than 30%. Comparisons of various clinical and imaging parameters revealed that the mean age at surgery was significantly lower in patients in the excellent recovery group than that in the poor recovery group. Therefore, the authors repeated the same analyses after adjustment for age. Postoperative cervical range of motion (ROM) was significantly more reduced in the excellent recovery group than in the poor recovery group. There was a significant positive correlation between reduced cervical ROM and recovery rate in the poor recovery group. Conclusions. Dynamic stress may deteriorate functional recovery of the degenerated spinal cord even after sufficient decompression. Postoperative preservation of cervical ROM may not always be beneficial for neurological recovery in patients with CSM.

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Pathognomonic radiological signs for predicting prognosis in patients with chronic atlantoaxial rotatory fixation

Ishii Ken, Chiba Kazuhiro, Maruiwa Hirofumi, Nakamura Masaya, Matsumoto Morio, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 ( 5 ) 385 - 391 2006.11

ISSN 1547-5654

Object. The authors conducted a study to assess the correlation between radiological features and clinical courses in patients with chronic atlantoaxial rotatory fixation (AARF) and to determine diagnostic imaging signs for predicting prognosis. Methods. There were 24 patients (eight boys and 16 girls) whose mean age was 7.8 years (range 4-14 years) and in whom AARF was diagnosed. The mean follow-up duration was 3.7 years (range 5 weeks-12 years). There were two groups of patients: 15 patients who visited the hospital less than 8 weeks after symptom (torticollis) onset comprised the acute group, and nine patients in whom the diagnosis of AARF was established later than 3 months after symptom onset comprised the chronic group. The chronic group was divided into two subgroups: those in whom the closed reduction could be achieved and those in whom it could not. Clinical data and radiographic studies, including plain radiographs and plain and three-dimensional (3D) computed tomography (CT) reconstructions, were reviewed retrospectively. A deformity of the superior C-2 facet joint was frequently observed in the group of patients with chronic AARF (p < 0.0001). This sign represented a risk factor for recurrent dislocation (p = 0.0003, Fisher exact test). Prominent lateral inclination of C-1 was an impeding factor for reduction of chronic AARF (p < 0.0001, analysis of variance with Fisher post hoc test). Greater than 20° of lateral inclination of the atlas indicated an irreducible subluxation (p = 0.0023, Fisher exact test). Conclusions. Both facet joint deformity and lateral inclination observed on 3D CT reconstructions can be useful signs to predict the prognosis and the treatment of choice in patients with chronic AARFs.

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Posterior osteotomy and instrumentation for thoracolumbar kyphosis in patients with achondroplasia

Qi Xin, Matsumoto Morio, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki

Spine 31 ( 17 ) 2006.08

ISSN 0362-2436

STUDY DESIGN. A retrospective case series of surgically treated achondroplastic patients with severe thoracolumbar kyphosis. OBJECTIVE. To evaluate the outcome of surgical treatment for thoracolumbar kyphosis in patients associated with achondroplasia presenting with paraparesis. SUMMARY OF BACKGROUND DATA. Thoracolumbar kyphosis is one of the frequent skeletal manifestations in patients with achondroplasia. Few papers have been published on the surgical treatment of this condition, especially in skeletally mature patients. METHODS. Four patients with achondroplasia who developed neurologic deficit due to severe thoracolumbar kyphosis and underwent surgical treatment were evaluated (mean age, 32.5 years; mean follow-up, 3.0 years). Posterior osteotomy with segmental instrumentation was performed in all cases. The surgical procedures included pedicle subtraction osteotomy in 2 patients without a hypoplastic apical vertebra and spondylectomy with reconstruction of the anterior column in 2 patients with a hypoplastic apical vertebra. Neurologic outcomes (JOA scores), correction of kyphosis, and operative complications were assessed. RESULTS. All patients had gait disturbance, and 2 patients were unambulatory before surgery. The average preoperative JOA score was 5.8 points, which was improved to 9.3 points at the final follow-up (mean recovery rate, 75%). All patients obtained neurologic improvement and became ambulatory either with or without crutches after surgery. The mean preoperative kyphotic angle was 96.3° (range, 57°-117°). The postoperative angles averaged 55.3° (range, 30°-110°), yielding a mean correction rate of 43.6%. Neither loss of correction nor pseudarthrosis has been observed during the follow-up period. Partial nerve root laceration and dural tear resulting in transient postoperative muscle weakness were observed in 2 patients as complications. CONCLUSIONS. Posterior spinal osteotomy with segmental instrumentation is a reasonable surgical option for thoracolumbar kyphosis in patients with achondroplasia. Modification of the surgical procedures depending on the presence or absence of the dysplastic changes of the apical vertebra is necessary to obtain optimal results. ©2006, Lippincott Williams & Wilkins, Inc.

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Pleomorphic xanthoastrocytoma of the spinal cord

Nakamura Masaya, Chiba Kazuhiro, Matsumoto Morio, Ikeda Eiji, Toyama Yoshiaki

Journal of Neurosurgery: Spine 5 ( 1 ) 72 - 75 2006.07

ISSN 1547-5654

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Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury

Okada Seiji, Nakamura Masaya, Katoh Hiroyuki, Miyao Tamaki, Shimazaki Takuya, Ishii Ken, Yamane Junichi, Yoshimura Akihiko, Iwamoto Yukihide, Toyama Yoshiaki, Okano Hideyuki

Nature Medicine 12 ( 7 ) 829 - 834 2006.07

ISSN 1078-8956

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3^-/-, Nes-Socs3^-/-). Reactive astrocytes in Nes-Stat3^-/- mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3^-/- mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. © 2006 Nature Publishing Group.

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Microendoscopic partial resection of the sacral ala to relieve extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel

Matsumoto Morio, Chiba Kazuhiro, Ishii Ken, Watanabe Kota, Nakamura Masaya, Toyama Yoshiaki

Journal of Neurosurgery: Spine 4 ( 4 ) 342 - 346 2006.04

ISSN 1547-5654

The authors report the cases of three patients with L-5 radiculopathy caused by extraforaminal entrapment of the L-5 spinal nerve at the lumbosacral tunnel; this structure comprises the lumbosacral ligament, the sacral ala, and the L-5 and S-1 vertebral bodies. All three patients suffered severe leg pain and neurological deficits compatible with L-5 radiculopathy. Decompressive surgery involved the microendoscopic partial resection of the sacral ala along the L-5 spinal nerve. All patients experienced immediate pain relief postoperatively. Microendoscopic partial resection of the sacral ala is an effective and minimally invasive surgical option for patients with extraforaminal entrapment of the L-5 spinal nerve.

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Lecithinized superoxide dismutase (PC-SOD) improved spinal cord injury-induced motor dysfunction through suppression of oxidative stress and enhancement of neurotrophic factor production

Takenaga Mitsuko, Ohta Yuki, Tokura Yukie, Hamaguchi Akemi, Nakamura Masaya, Okano Hideyuki, Igarashi Rie

Journal of Controlled Release 110 ( 2 ) 283 - 289 2006.01

ISSN 0168-3659

PC-SOD (lecithinized superoxide dismutase) is a derivative of human Cu, Zn-SOD conjugated with 4 molecules of lecithin, yet having the enzyme activity of scavenging superoxide anion (O₂^-). Intravenous administration of PC-SOD promoted the recovery from spinal cord injury (SCI)-induced motor dysfunction in a dose-dependent manner in rat model, when evaluated by BBB (Basso Beattie Bresnahan) score. Even when given at 24 h after SCI, PC-SOD (1 mg/kg) significantly improved motor dysfunction. Distribution study demonstrated that PC-SOD gradually accumulated to the injured site. Enzyme-linked immunoassay revealed that PC-SOD prevented quantitative loss of neurons, astrocytes, and oligodendrocytes. PC-SOD inhibited SCI-induced oxidative stress, such as the decrease of free sulfhydryl residue, acetylcholine esterase activity, and the increase of lipid peroxidation. PC-SOD increased the production of neuroprotective factors. HIF-1α gene expression increased following SCI, and PC-SOD further increased it. In conclusion, PC-SOD gradually accumulated and retained at the damaged site to scavenge excessive O ₂^-, and suppressed neuronal death through reducing oxidative stress, increasing neuroprotective factor production and HIF-1α gene expression. © 2005 Elsevier B.V. All rights reserved.

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Disease progression of human SOD1 (G93A) transgenic ALS model rats

Matsumoto Arifumi, Okada Yohei, Nakamichi Masanori, Nakamura Masaya, Toyama Yoshiaki, Sobue Gen, Nagai Makiko, Aoki Masashi, Itoyama Yasuto, Okano Hideyuki

Journal of Neuroscience Research 83 ( 1 ) 119 - 133 2006.01

ISSN 0360-4012

The recent development of a rat model of amyotrophic lateral sclerosis (ALS) in which the rats harbor a mutated human SOD1 (G93A) gene has greatly expanded the range of potential experiments, because the rats' large size permits biochemical analyses and therapeutic trials, such as the intrathecal injection of new drugs and stem cell transplantation. The precise nature of this disease model remains unclear. We described three disease phenotypes: the forelimb-, hindlimb-, and general-types. We also established a simple, non-invasive, and objective evaluation system using the body weight, inclined plane test, cage activity, automated motion analysis system (SCANET), and righting reflex. Moreover, we created a novel scale, the Motor score, which can be used with any phenotype and does not require special apparatuses. With these methods, we uniformly and quantitatively assessed the onset, progression, and disease duration, and clearly presented the variable clinical course of this model; disease progression after the onset was more aggressive in the forelimb-type than in the hindlimb-type. More importantly, the disease stages defined by our evaluation system correlated well with the loss of spinal motor neurons. In particular, the onset of muscle weakness coincided with the loss of approximately 50% of spinal motor neurons. This study should provide a valuable tool for future experiments to test potential ALS therapies. © 2005 Wiley-Liss, Inc.

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Ischemia-induced disturbance of neuronal network function in the rat spinal cord analyzed by voltage-imaging

Fukuda K., Okada Y., Yoshida H., Aoyama R., Nakamura M., Chiba K., Toyama Y.

Neuroscience 140 ( 4 ) 1453 - 1465 2006

ISSN 0306-4522

Using a voltage-imaging technique, we analyzed the acute effect of ischemia, hypoxia and hypoglycemia on the neuronal network function of the rat spinal cord. Ischemic, hypoxic, or hypoglycemic stress was loaded to spinal cord slices with an oxygen- and glucose-free, oxygen-free, or glucose-free mock cerebrospinal fluid, respectively. Depolarizing signals in the dorsal horn, induced by dorsal root stimulation, consisted of fast (pre-synaptic) and slow (post-synaptic) components. The slow component was attenuated much more than the fast component under an ischemic condition (P<0.0002). Post-synaptic neuronal activities in lamina III-IV were suppressed earlier than those in lamina I-II. The nerve fiber was relatively resistant to ischemia. As long as the fast component was preserved in the dorsal horn, the suppression of the fast and slow components was reversible. There was a significant difference (P<0.05) in the recovered slow component sizes between the group in which the fast component was suppressed by more than 20% by ischemia and the group in which the suppression was less than 20%. Further prolonged stress irreversibly eliminated most of the slow component, and attenuated the fast component (to 59±8%) accompanied by cellular damage in histology. Suppression of neural activity by hypoxic or hypoglycemic stress was less prominent than that by ischemia. Prolonged ischemic stress suddenly and irreversibly eliminated depolarizing signals in the ventral horn accompanied by morphological damage of motoneurons. Immunohistochemical staining was negative for apoptosis. We have, for the first time, analyzed the processes of spinal cord disturbance induced by ischemia, hypoxia and hypoglycemia at the neuronal network level by directly observing the regional neuronal network activities within the spinal cord. We conclude that synaptic transmission in the dorsal horn, especially in deep regions, is vulnerable and first affected by these stresses. Severe ischemic stress induces irreversible dysfunction of neurons accompanied by eventual cell death in both dorsal and ventral horns. © 2006 IBRO.

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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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Spinal kyphosis causes demyelination and neuronal loss in the spinal cord

Shimizu Kentaro, Nakamura Masaya, Nishikawa Yuji, Hijikata Sadahisa, Chiba Kazuhiro, Toyama Yoshiaki

Spine 30 ( 21 ) 2388 - 2392 2005.11

ISSN 0362-2436

Study Design. Histologic changes in the spinal cord caused by progressive spinal kyphosis were assessed using a new animal model. Objectives. To evaluate the effects of chronic compression associated with kyphotic deformity of the cervical spine on the spinal cord. Summary of Background Data. The spinal cord has remarkable ability to resist chronic compression, however, delayed paralysis is sometimes seen following the development of spinal kyphosis. In the past, no animal model to clarify the mechanism of spinal cord damage due to spinal kyphotic deformity has been available. Methods. Laminectomy and bilateral facetectomy at the C4-C5 level was performed in 52 Japanese small game fowls. Histologic changes in the spinal cord associated with progressive kyphotic deformity were examined at different time points after surgery in each animal. The degree of spinal cord flattening and the severity of demyelination in histologic sections were quantitatively evaluated using an image analyzer, and their association with the kyphotic angle was analyzed. Changes in the microvascular distribution in the spinal cord were also examined by microangiography. Results. In all operated animals, progressive kyphosis developed reproducibly. The kyphotic angle increased gradually until 3 weeks after surgery and stabilized thereafter. There was a significant correlation between the kyphotic angle and the degree of spinal cord flattening. The spinal cord was compressed most intensely at the apex of the kyphosis, where demyelination of the anterior funiculus as well as neuronal loss and atrophy of the anterior horn were observed. Demyelination progressed as the kyphotic deformity became more severe, initially affecting the anterior funiculus and later extending to the lateral and then the posterior funiculus. Angiography revealed a decrease of the vascular distribution at the ventral side of the compressed spinal cord. Conclusions. Progressive kyphosis of the cervical spine resulted in demyelination of nerve fibers in the funiculi and neuronal loss in the anterior horn due to chronic compression of the spinal cord. These histologic changes seem to be associated with both continuous mechanical compression and vascular changes in the spinal cord. ©2005, Lippincott Williams & Wilkins, Inc.

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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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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.

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