Details of a Researcher - Nakamura, Masaya

Papers - Nakamura, Masaya

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Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice

Nori Satoshi, Okada Yohei, Yasuda Akimasa, Tsuji Osahiko, Takahashi Yuichiro, Kobayashi Yoshiomi, Fujiyoshi Kanehiro, Koike Masato, Uchiyama Yasuo, Ikeda Eiji, Toyama Yoshiaki, Yamanaka Shinya, Nakamura Masaya, Okano Hideyuki

Proceedings of the National Academy of Sciences of the United States of America 108 ( 40 ) 16825 - 16830 2011.10

ISSN 0027-8424

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncellautonomous (trophic) effects, including synapse formation between hiPSC-NS-derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS-grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.

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Cell Therapy for Spinal Cord Injury by Neural Stem/Progenitor Cells Derived from iPS/ES Cells

Tsuji Osahiko, Miura Kyoko, Fujiyoshi Kanehiro, Momoshima Suketaka, Nakamura Masaya, Okano Hideyuki

Neurotherapeutics 8 ( 4 ) 668 - 676 2011.10

ISSN 1933-7213

Reports of functional recovery from spinal cord injury after the transplantation of rat fetus-derived neural stem cells and embryonic stem cells has raised great expectations for the successful clinical use of stem cell transplantation therapy. However, the ethical issues involved in destroying human embryos or fertilized oocytes to obtain stem cells have been a major obstacle to developing clinically useful stem cell sources, and the transplantation of stem cells isolated from other human embryonic tissues has not yet been developed for use in clinical applications. Recently, induced pluripotent stem cells, which can serve as a source of cells for autologous transplantation, have been attracting a great deal of attention as a clinically viable alternative to stem cells obtained directly from tissues. In this review, we outline the neural induction of mouse embryonic stem cells and induced pluripotent stem cells, their therapeutic efficacy in spinal cord injury, and their safety in vivo. © 2011 The American Society for Experimental NeuroTherapeutics, Inc.

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Late instrumentation failure after total en bloc spondylectomy

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

Journal of Neurosurgery: Spine 15 ( 3 ) 320 - 327 2011.09

ISSN 1547-5654

Object. The object of this study was to investigate failures after spinal reconstruction following total en bloc spondylectomy (TES), related factors, and sequelae arising from such failures in patients with malignant spinal tumors. Methods. Fifteen patients (12 males and 3 females, with a mean age of 46.5 years) with malignant spinal tumors who underwent TES and survived for more than 1 year were included in this analysis (mean follow-up 41.5 months). Seven patients had primary tumors, including giant cell tumors in 4 patients, chordoma in 2, and Ewing sarcoma in 1. Eight patients had metastatic tumors, including thyroid cancer in 6 and renal cell cancer and malignant fibrous histiocytoma in 1 patient each. Seven patients without prominent paravertebral extension of the tumor were treated using a posterior approach alone, and 8 patients who exhibited prominent anterior or anterolateral extension of the tumors into the thoracic or abdominal cavity were treated using a combined anterior and posterior approach. Spinal reconstruction after tumor resection was performed using a combination of anterior structural support and posterior instrumentation. The relationship between instrumentation failure and clinical and radiographic factors, including age, sex, history of previous surgery, preoperative radiotherapy, tumor histology, tumor level, surgical approach, number of resected vertebrae, rod diameter, number of instrumented vertebrae, and cage subsidence, was investigated. Results. Six patients (40%) with spinal instrumentation failure were identified: rod breakage occurred in 3 patients, and breakage of both the rod and the cage, combined cage breakage and screw back-out, and endplate fracture arising from cage subsidence occurred in 1 patient each. All of these patients experienced acute or chronic back pain, but only 1 patient with a tumor recurrence experienced neurological deterioration upon instrumentation failure. Cage subsidence (≥ 5 mm), preoperative irradiation, and the number of instrumented vertebrae (≤ 4 vertebrae) were significantly related to late instrumentation failure. Conclusions. Late instrumentation failure was a frequent complication after TES. Although patients with instrumentation failure experienced back pain, the neurological sequelae were not catastrophic. For prevention, meticulous preparation of the graft site and a longer posterior fixation should be considered.

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Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn

Aoyama Ryoma, Okada Yasumasa, Yokota Shigefumi, Yasui Yutaka, Fukuda Kentaro, Shinozaki Yoshio, Yoshida Hideaki, Nakamura Masaya, Chiba Kazuhiro, Yasui Yukihiko, Kato Fusao, Toyama Yoshiaki

Pain 152 ( 9 ) 2085 - 2097 2011.09

ISSN 0304-3959

Extracellularly released adenosine triphosphate (ATP) modulates sensory signaling in the spinal cord. We analyzed the spatiotemporal profiles of P2X receptor-mediated neuronal and glial processing of sensory signals and the distribution of P2X receptor subunits in the rat dorsal horn. Voltage imaging of spinal cord slices revealed that extracellularly applied ATP (5-500 μM), which was degraded to adenosine and acting on P1 receptors, inhibited depolarizing signals and that it also enhanced long-lasting slow depolarization, which was potentiated after ATP was washed out. This post-ATP rebound potentiation was mediated by P2X receptors and was more prominent in the deep than in the superficial layer. Patch clamp recording of neurons in the superficial layer revealed long-lasting enhancement of depolarization by ATP through P2X receptors during the slow repolarization phase at a single neuron level. This depolarization pattern was different from that in voltage imaging, which reflects both neuronal and glial activities. By immunohistochemistry, P2X ₁ and P2X ₃ subunits were detected in neuropils in the superficial layer. The P2X ₅ subunit was found in neuronal somata. The P2X ₆ subunit was widely expressed in neuropils in the whole gray matter except for the dorsal superficial layer. Astrocytes expressed the P2X ₇ subunit. These findings indicate that extracellular ATP is degraded into adenosine and prevents overexcitation of the sensory system, and that ATP acts on pre- and partly on postsynaptic neuronal P2X receptors and enhances synaptic transmission, predominantly in the deep layer. Astrocytes are involved in sensitization of sensory network activity more importantly in the superficial than in the deep layer. © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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Prevalence and characteristics of chronic musculoskeletal pain in Japan

Nakamura Masaya, Nishiwaki Yuji, Ushida Takahiro, Toyama Yoshiaki

Journal of Orthopaedic Science 16 ( 4 ) 424 - 432 2011.07

ISSN 0949-2658

Background: This cross-sectional study was conducted to obtain epidemiologic data on chronic musculoskeletal pain in the Japanese people, and with it a better understanding of the actual conditions and problems involved. Methods: A questionnaire covering basic information, chronic musculoskeletal pain, daily life, quality of life, and social loss was prepared and mailed to 11507 individuals aged 18 years or older. Subjects were selected randomly nationwide in accordance with the demographic composition of Japan. Results: The prevalence of chronic musculoskeletal pain was 15.4%. The prevalence was highest in people in their 30s to 50s. Pain occurred most frequently in the low back, neck, shoulder, and knee. Among symptomatic subjects, 42% sought treatment, by visiting a medical institution (19%), taking folk remedies (20%), or both (3%). Treatment was generally prolonged, with 70% of those treated reporting treatment durations of more than a year. Although 69% reported that their symptoms had improved, 30% reported unchanged or aggravated symptoms and dissatisfaction with treatment. Among symptomatic subjects, a high percentage of both men and women had lost jobs, left school, been absent from work or school, or had changed jobs. Basic activities of daily living (ADL) were disturbed in men, and the instrumental ADL (IADL) score was low in women. SF-36 scale scores were significantly lower in every area for subjects with chronic pain. Conclusions: Chronic musculoskeletal pain does not necessarily improve even with prolonged treatment. It adversely affects daily life and both physical and mental health. Because those suffering pain often increasingly need assistance in daily activities, people around them are also affected. The therapeutic system and treatment procedures for chronic musculoskeletal pain merit prompt review. © 2011 The Author(s).

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Long-term surgical outcomes of idiopathic spinal cord herniation

Nakamura Masaya, Fujiyoshi Kanehiro, Tsuji Osahiko, Watanabe Kota, Tsuji Takashi, Ishii Ken, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Orthopaedic Science 16 ( 4 ) 347 - 351 2011.07

ISSN 0949-2658

Background: Because of the lack of long-term postoperative follow-up studies of idiopathic spinal cord herniation (ISCH), there is little information about the long-term effectiveness and complications of the dural defect enlargement in patients with ISCH. The purpose of this study is to determine the long-term effectiveness of this procedure. Methods: Sixteen patients with ISCH were treated surgically by enlargement of the dural defect. The patient's neurological status and surgical outcome were evaluated by the JOA scores for thoracic myelopathy and the recovery rate (mean follow-up period 9.6 years). Correlations between the surgical outcomes and patients' age and duration of disease were assessed retrospectively. The patients were also divided into two groups based on the location of the dural defect: the ventro-lateral (VL) group and the ventral (V) group. The difference in the duration of disease, preoperative JOA score, and the recovery rate were compared between the two groups. Results: There was no recurrence of ISCH after surgery. The mean recovery rate was 42.6%. There was a significant correlation between the patient's age and the recovery rate, and between the duration of disease and the recovery rate. The median recovery rate was significantly lower in the V group than in the VL group. There were no complications related to CSF leakage after surgery. Conclusions: Long-term surgical outcomes of enlargement of the dural defect for ISCH were stable and favorable without recurrences or any complications. This procedure should be considered for patients with ISCH before their neurological deficit worsens, especially for the patients in whom the dural defect is located at the ventral part of the dural canal. © 2011 The Author(s).

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The IRE1α-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix

Tohmonda Takahide, Miyauchi Yoshiteru, Ghosh Rajarshi, Yoda Masaki, Uchikawa Shinichi, Takito Jiro, Morioka Hideo, Nakamura Masaya, Iwawaki Takao, Chiba Kazuhiro, Toyama Yoshiaki, Urano Fumihiko, Horiuchi Keisuke

EMBO Reports 12 ( 5 ) 451 - 457 2011.05

ISSN 1469-221X

During skeletal development, osteoblasts produce large amounts of extracellular matrix proteins and must therefore increase their secretory machinery to handle the deposition. The accumulation of unfolded protein in the endoplasmic reticulum induces an adoptive mechanism called the unfolded protein response (UPR). We show that one of the most crucial UPR mediators, inositol-requiring protein 1α (IRE1α), and its target transcription factor X-box binding protein 1 (XBP1), are essential for bone morphogenic protein 2-induced osteoblast differentiation. Furthermore, we identify Osterix (Osx, a transcription factor that is indispensible for bone formation) as a target gene of XBP1. The promoter region of the Osx gene encodes two potential binding motifs for XBP1, and we show that XBP1 binds to these regions. Thus, the IRE1α-XBP1 pathway is involved in osteoblast differentiation through promoting Osx transcription. © 2011 European Molecular Biology Organization.

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Schwann cell plasticity after spinal cord injury shown by neural crest lineage tracing

Nagoshi Narihito, Shibata Shinsuke, Hamanoue Makoto, Mabuchi Yo, Matsuzaki Yumi, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

GLIA 59 ( 5 ) 771 - 784 2011.05

ISSN 0894-1491

After spinal cord injury (SCI), various cell types are recruited to the lesion site, including Schwann cells, which originate in the neural crest and normally myelinate axons in the peripheral nervous system. Here, we investigated the differentiation states, migration patterns, and roles of neural crest derivatives following SCI, using two transgenic mouse lines carrying neural crest-specific reporters, P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. In these mice, EGFP is expressed only in the neural crest cell lineage. Immunohistochemical analysis revealed that most of the EGFP⁺ cells that infiltrated the lesion site after SCI were Schwann cells. Seven days after SCI, the P0-positive, mature Schwann cells residing at the nerve roots had dedifferentiated into P0^-/p75⁺ immature Schwann cells, which proliferated and began migrating into the lesion site. The dedifferentiation of the Schwann cells was corroborated by their expression of phosphorylated c-Jun, which promotes dedifferentiation and inhibits the expression of myelin-associated genes in the peripheral nerves. Thereafter, the number of EGFP⁺/p75⁺ immature Schwann cells decreased and that of EGFP⁺/P0⁺ mature cells increased gradually, indicating that the cells redifferentiated into mature Schwann cells within the lesion site. This study draws on the advantages offered by transgenic mouse lines bearing a genetic cell-lineage marker and extends previous work by describing the origins and behavior of the neural crest-derived cells that contribute to endogenous repair after SCI. This process, involving Schwann cell plasticity, is a novel repair mechanism for the lesioned mammalian spinal cord. © 2011 Wiley-Liss, Inc.

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A rare case of spinal dumbbell tanycytic ependymoma

Ishihama Hiroko, Nakamura Masaya, Funao Hiroki, Ishii Ken, Matsumoto Morio, Toyama Yoshiaki, Chiba Kazuhiro

Spine 36 ( 9 ) 2011.04

ISSN 0362-2436

Study Design.: Case report. OBJECTIVE:: To report an extremely rare case of spinal dumbbell-type tanycyticependymoma. Summary of Background Data.: Only two previous cases of a dumbbell-type tanycyticependymoma in the spinal cordhave been reported. Methods.: A 40-year-old female presented with low back pain and numbness of the left leg. Magnetic resonance imaging revealed a dumbbell tumor at the Th10-11 level that compressed the spinal cord extensively. The diagnosis of extradural dumbell spinal tumor was made, and a total tumor excision was performed with a thoracic 10-11 laminectomy. Results.: After surgery, the patient's low back pain and numbness disappeared. Detailed immunohistological examinations confirmed the diagnosis of tanycyticependymoma. At 16 months, there was no evidence of tumor recurrence and no further treatment was needed. Conclusion.: A rare case of spinal dumbbell-type tanycyticependy-moma was presented. Detailed histologic examinations are essential to differentiate tanycyticependymoma from other tumors such as schwannoma and pilocyticastrocytoma. © 2011, Lippincott Williams & Wilkins.

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Severe progressive scoliosis due to huge subcutaneous cavernous hemangioma

Ogura Yoji, Watanabe Kota, Hosogane Naobumi, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Scoliosis 6 ( 1 ) 2011.03

Cavernous hemangioma consists mainly of congenital vascular malformations present before birth and gradually increasing in size with skeletal growth. A small number of patients with cavernous hemangioma develop scoliosis, and surgical treatment for the scoliosis in such cases has not been reported to date. Here we report a 12-year-old male patient with severe progressive scoliosis due to a huge subcutaneous cavernous hemangioma, who underwent posterior correction and fusion surgery. Upon referral to our department, radiographs revealed a scoliosis of 85° at T6-L1 and a kyphosis of 58° at T4-T10. CT and MR images revealed a huge hemangioma extending from the subcutaneous region to the paraspinal muscles and the retroperitoneal space and invading the spinal canal. Posterior correction and fusion surgery using pedicle screws between T2 and L3 were performed. Massive hemorrhage from the hemangioma occurred during the surgery, with intraoperative blood loss reaching 2800 ml. The scoliosis was corrected to 59°, and the kyphosis to 45° after surgery. Seven hours after surgery, the patient suffered from hypovolemic shock and disseminated intravascular coagulation due to postoperative hemorrhage from the hemangioma. The patient developed sensory and conduction aphasia caused by cerebral hypoxia during the shock on the day of the surgery. At present, two years after the surgery, although the patient has completely recovered from the aphasia. This case illustrates that, in correction surgery for scoliosis due to huge subcutaneous cavernous hemangioma, intraoperative and postoperative intensive care for hemodynamics should be performed, since massive hemorrhage can occur during the postoperative period as well as the intraoperative period.© 2011 Ogura et al; licensee BioMed Central Ltd.

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Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome

Watanabe Kota, Okada Eijiro, Kosaki Kenjiro, Tsuji Takashi, Ishii Ken, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki, Matsumoto Morio

Journal of Pediatric Orthopaedics 31 ( 2 ) 186 - 193 2011.03

ISSN 0271-6798

Background: Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. Methods: Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3±4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. Results: The mean preoperative Cobb angle was 102.8±16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49±16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. Conclusions: Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. Level of evidence: Level IV. © 2011 by Lippincott Williams & Wilkins.

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Remodeling of C2 facet deformity prevents recurrent subluxation in patients with chronic atlantoaxial rotatory fixation

Ishii Ken, Matsumoto Morio, Momoshima Suketaka, Watanabe Kota, Tsuji Takashi, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Spine 36 ( 4 ) 2011.02

ISSN 0362-2436

Study Design. A retrospective case series. Objective. To propose a novel treatment strategy for chronic atlantoaxial rotatory fixation (AARF). Summary Of Background Data. Treatment strategy for chronic or recurrent AARF remains controversial. We have previously reported that a deformity of the superior facet of the axis (C2 facet deformity), which is frequently observed in patients with chronic AARFs, is a risk factor for recurrent dislocation. In this article, we report seven consecutive cases of chronic AARF who underwent closed manipulation followed by external halo fixation and maintained good reduction with the remodeling of the C2 facet deformity. Methods. Seven girls with a chronic AARF who sustained torticollis for an average of 4.6 months after the onset were referred to our clinic. Closed manipulation by careful manipulation under general anesthesia followed by external immobilization with a halo vest was performed in all cases. Radiographic findings and clinical courses were retrospectively reviewed with approvals by the institutional review board. Results. Three-dimensional computed tomography images before reduction revealed persistent atlantoaxial subluxation and the C2 facet deformity in the dislocated side in all cases. Follow-up three-dimensional computed tomographic scans demonstrated the remodeling of the C2 facet deformity at an average of 2.8 months after successful reduction of subluxation. Subsequently, the halo vests were removed and gentle neck range of motion exercise was started in all cases. The normal cervical range of motion was obtained 2 weeks after the removal of halo vests in five cases, whereas the range of motion remained limited in two cases. At a mean follow-up of 17.4 months, neither symptoms nor recurrence of subluxation occurred in all cases. Conclusion. Chronic irreducible and recurrent unstable AARF can be managed successfully by careful closed manipulation followed by halo fixation, if the C1 and C2 have not been osseously fused. The remodeling of the C2 facet deformity detected on follow-up CT scans can be a useful radiographic parameter to determine the appropriate period of halo fixation in this new treatment strategy obviating the need for surgical intervention. Copyright © 2011 Lippincott Williams & Wilkins.

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Intramedullary spinal cord cavernous hemangiomas

Ishii Ken, Nakamura Masaya

Brain and Nerve 63 ( 1 ) 27 - 30 2011.01

ISSN 1881-6096

Reduced postoperative wound pain after lumbar spinous process-splitting laminectomy for lumbar canal stenosis

Watanabe Kota, Matsumoto Morio, Ikegami Takeshi, Nishiwaki Yuji, Tsuji Takashi, Ishii Ken, Ogawa Yuto, Takaishi Hironari, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro

Journal of Neurosurgery: Spine 14 ( 1 ) 51 - 58 2011.01

ISSN 1547-5654

Object. To reduce intraoperative damage to the posterior supporting structures of the lumbar spine during decompressive surgery for lumbar canal stenosis (LCS), lumbar spinous process-splitting laminectomy (LSPSL or split laminectomy) was developed. This prospective, randomized, controlled study was conducted to clarify whether the split laminectomy decreases acute postoperative wound pain compared with conventional laminectomy. Methods. Forty-one patients with LCS were enrolled in this study. The patients were randomly assigned to either the LSPSL group (22 patients) or the conventional laminectomy group (19 patients). Questionnaires regarding wound pain (intensity, depth, and duration) and activities of daily living (ADL) were administered at postoperative days (PODs) 3 and 7. Additionally, the authors evaluated the pre- and postoperative serum levels of C-reactive protein and creatine phosphokinase, the amount of pain analgesics used during a 3-day postoperative period, and the muscle atrophy rate measured on 1-month postsurgical MR images. Results. Data obtained in patients in the LSPSL group and in 16 patients in the conventional laminectomy group were analyzed. The mean visual analog scale for wound pain on POD 7 was significantly lower in the LSPSL group (16 ± 17 mm vs 34 ± 31 mm, respectively; p = 0.04). The mean depth-of-pain scores on POD okinase level was significantly lower in the LSPSL group (126 ± 93 U/L) than in the other group (207 ± 150 U/L) (p = 0.02); on POD 7, the mean serum C-reactive protein level was significantly lower in the LSPSL group (1.1 ± 0.6 mg/dl) than in the conventional laminectomy group (1.9 ± 1.5 mg/dl) (p = 0.04). The number of pain analgesics taken during the 3-day postoperative period was lower in the LSPSL group than in the conventional laminectomy group (1.7 ± 1.3 tablets vs 2.3 ± 2.4 tablets, respectively; p = 0.22). The mean muscle atrophy rate was also significantly lower in the LSPSL group (24% ± 15% vs 43% ± 22%; p = 0.004). Conclusions. Lumbar spinous process-splitting laminectomy for the treatment of LCS reduced acute postoperative wound pain and prevented postoperative muscle atrophy compared with conventional laminectomy, possibly because of minimized damage to the paraspinal muscles.

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Schwann-spheres derived from injured peripheral nerves in adult mice - their in vitro characterization and therapeutic potential

Takagi Takehiko, Ishii Ken, Shibata Shinsuke, Yasuda Akimasa, Sato Momoka, Nagoshi Narihito, Saito Harukazu, Okano Hirotaka J., Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 6 ( 6 ) 2011

Multipotent somatic stem cells have been identified in various adult tissues. However, the stem/progenitor cells of the peripheral nerves have been isolated only from fetal tissues. Here, we isolated Schwann-cell precursors/immature Schwann cells from the injured peripheral nerves of adult mice using a floating culture technique that we call "Schwann-spheres." The Schwann-spheres were derived from de-differentiated mature Schwann cells harvested 24 hours to 6 weeks after peripheral nerve injury. They had extensive self-renewal and differentiation capabilities. They strongly expressed the immature-Schwann-cell marker p75, and differentiated only into the Schwann-cell lineage. The spheres showed enhanced myelin formation and neurite growth compared to mature Schwann cells in vitro. Mature Schwann cells have been considered a promising candidate for cell-transplantation therapies to repair the damaged nervous system, whereas these "Schwann-spheres" would provide a more potential autologous cell source for such transplantation. © 2011 Takagi et al.

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Central neuropathic pain after surgical resection in patients with spinal intramedullary tumor

Nakamura Masaya, Tsuji Osahiko, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Clinical Neurology 51 ( 11 ) 937 - 938 2011

ISSN 0009-918X

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Novel concept of motor functional analysis for spinal cord injury in adult mice

Nakamura Masaya, Shinozaki Munehisa, Takahashi Yuichiro, Mukaino Masahiko, Saito Nobuhito, Toyama Yoshiaki, Okano Hideyuki

Journal of Biomedicine and Biotechnology 2011 2011

ISSN 1110-7243

In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open-field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open-field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function. © 2011 Munehisa Shinozaki et al.

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Comparative study of methods for administering neural stem/progenitor cells to treat spinal cord injury in mice

Takahashi Yuichiro, Tsuji Osahiko, Kumagai Gentaro, Hara Chikako Miyauchi, Okano Hirotaka James, Miyawaki Atsushi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Cell Transplantation 20 ( 5 ) 727 - 739 2011

ISSN 0963-6897

To investigate potential cures for spinal cord injury (SCI), several researchers have transplanted neural stem/progenitor cells (NS/PCs) into the injured spinal cord by different procedures, including intralesional (IL), intrathecal (IT), and intravenous (IV) injection. However, there are no reports quantifying or comparing the number of cells successfully transplanted to the lesion site by each procedure in vivo. The purpose of the present study was to determine the optimal method of cell transplantation to the SCI site in terms of grafted cell survival and safety. For this purpose, we developed mouse NS/PCs that expressed a novel Venus-luciferase fusion protein that enabled us to detect a minimum of 1,000 grafted cells in vivo by biolumines-cence imaging (BLI). After inducing contusive SCI at the T10 level in mice, NS/PCs were transplanted into the injured animals three different ways: by IL, IT, or IV injection. Six weeks after the transplantation, BLI analysis showed that in the IL group, the luminescence intensity of the grafted cells had decreased to about 10% of its initial level, and appeared at the site of injury. In the IT group, the luminescence of the grafted cells, which was distributed throughout the entire subarachnoid space immediately after transplantation, was detected at the injured site 1 week later, and by 6 weeks had gradually decreased to about 0.3% of its initial level. In the IV group, no grafted cells were detected at the site of injury, but all of these mice showed luminescence in the bilateral chest, suggesting pulmonary embolism. In addition, one third of these mice died immediately after the IV injection. In terms of grafted cell survival and safety, we conclude that the IL application of NS/PCs is the most effective and feasible method for transplanting NS/PCs into the SCI site.

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Transplantation of human neural stem/progenitor cells overexpressing galectin-1 improves functional recovery from focal brain ischemia in the mongolian gerbil

Yamane Junichi, Ishibashi Satoru, Sakaguchi Masanori, Kuroiwa Toshihiko, Kanemura Yonehiro, Nakamura Masaya, Miyoshi Hiroyuki, Sawamoto Kazunobu, Toyama Yoshiaki, Mizusawa Hidehiro, Okano Hideyuki

Molecular Brain 4 ( 1 ) 2011

Transplantation of human neural stem/progenitor cells (hNSPCs) is a promising method to regenerate tissue from damage and recover function in various neurological diseases including brain ischemia. Galectin-1(Gal1) is a lectin that is expressed in damaged brain areas after ischemia. Here, we characterized the detailed Gal1 expression pattern in an animal model of brain ischemia. After brain ischemia, Gal1 was expressed in reactive astrocytes within and around the infarcted region, and its expression diminished over time. Previously, we showed that infusion of human Gal1 protein (hGal1) resulted in functional recovery after brain ischemia but failed to reduce the volume of the ischemic region. This prompted us to examine whether the combination of hNSPCs-transplantation and stable delivery of hGal1 around the ischemic region could reduce the ischemic volume and promote better functional recovery after brain ischemia. In this study, we transplanted hNSPCs that stably overexpressed hGal1 (hGal1-hNSPCs) in a model of unilateral focal brain ischemia using Mongolian gerbils. Indeed, we found that transplantation of hGal1-hNSPCs both reduced the ischemic volume and improved deficits in motor function after brain ischemia to a greater extent than the transplantation of hNSPCs alone. This study provides evidence for a potential application of hGal1 with hNSPCs-transplantation in the treatment of brain ischemia. © 2011Yamane et al; licensee BioMed Central Ltd.

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The dual origin of the peripheral olfactory system

Katoh Hiroyuki, Shibata Shinsuke, Fukuda Kimiko, Sato Momoka, Satoh Etsuko, Nagoshi Narihito, Minematsu Takeo, Matsuzaki Yumi, Akazawa Chihiro, Toyama Yoshiaki, Nakamura Masaya, Okano Hideyuki

Molecular Brain 4 ( 1 ) 2011

Abstract. Background: The olfactory epithelium (OE) has a unique capacity for continuous neurogenesis, extending axons to the olfactory bulb with the assistance of olfactory ensheathing cells (OECs). The OE and OECs have been believed to develop solely from the olfactory placode, while the neural crest (NC) cells have been believed to contribute only the underlying structural elements of the olfactory system. In order to further elucidate the role of NC cells in olfactory development, we examined the olfactory system in the transgenic mice Wnt1-Cre/Floxed-EGFP and P0-Cre/Floxed-EGFP, in which migrating NC cells and its descendents permanently express GFP, and conducted transposon-mediated cell lineage tracing studies in chick embryos. Results: Examination of these transgenic mice revealed GFP-positive cells in the OE, demonstrating that NC-derived cells give rise to OE cells with morphologic and antigenic properties identical to placode-derived cells. OECs were also positive for GFP, confirming their NC origin. Cell lineage tracing studies performed in chick embryos confirmed the migration of NC cells into the OE. Furthermore, spheres cultured from the dissociated cells of the olfactory mucosa demonstrated self-renewal and trilineage differentiation capacities (neurons, glial cells, and myofibroblasts), demonstrating the presence of NC progenitors in the olfactory mucosa. Conclusion: Our data demonstrates that the NC plays a larger role in the development of the olfactory system than previously believed, and suggests that NC-derived cells may in part be responsible for the remarkable capacity of the OE for neurogenesis and regeneration. © 2011Katoh et al; licensee BioMed Central Ltd.

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