Details of a Researcher - Nakamura, Masaya

Papers - Nakamura, Masaya

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In vivo tracing of neural tracts in tiptoe walking yoshimura mice by diffusion tensor tractography

Takano Morito, Komaki Yuji, Hikishima Keigo, Konomi Tsunehiko, Fujiyoshi Kanehiro, Tsuji Osahiko, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Spine 38 ( 2 ) 2013.01

ISSN 0362-2436

STUDY DESIGN.: Basic imaging experiment. OBJECTIVE.: To determine whether in vivo diffusion tensor tractography (DTT) can be used to evaluate the axonal disruption of the chronically compressed spinal cord in tiptoe walking Yoshimura (twy) mice. SUMMARY OF BACKGROUND DATA.: In cervical ossification of the posterior longitudinal ligament, axonal disruption results in motor and sensory functional impairment. Twy mice develop spontaneous calcification in the cervical ligaments, which causes chronic compression of the spinal cord. DTT is emerging as a powerful tool for tracing axonal fibers in vivo. METHODS.: Five twy mice were subjected to DTT at 6, 15, and 20 weeks of age. Magnetic resonance imaging was performed using a 7.0-Tesla magnet (Biospec 70/16; Billerica, MA) with a CryoProbe. Diffusion tensor images were analyzed using TrackVis (Massachusetts General Hospital, MA). Motor performance was evaluated by Rotarod treadmill test and Digigait analysis. Histological analysis was performed by hematoxylin-eosin staining and immunostaining for RT-97 and SMI-31. RESULTS.: High resolution DTT of twy mice in vivo was successful. A lower number of RT-97- or SMI-31-positive fibers were associated with more severe spinal cord compression, which was determined by observing the ligamentous calcification at the C2-C3 level in each twy mouse. The severity of canal stenosis based on magnetic resonance images was strongly correlated with the axial area of the spinal cord. The tract fiber (TF) ratio (the number of TFs at the C2-C3 level/the number of TFs at the C0-C1 level) was strongly correlated with the RT-97/SMI-31-positive area and with motor function (rotarod latency, stride length). Furthermore, a two-part linear regression analysis showed that canal stenosis around 50% to 60% caused a sharp decrease in the TF ratio before the deterioration of motor function. CONCLUSION.: We conclude that DTT could be useful for detecting the early changes associated with the compressed spinal cord in cervical ossification of the posterior longitudinal ligament. Copyright © 2013 Lippincott Williams & Wilkins.

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Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

Nakamura Masaya, Okano Hideyuki

Cell Research 23 ( 1 ) 70 - 80 2013.01

ISSN 1001-0602

Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients. © 2013 IBCB, SIBS, CAS All rights reserved.

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Long-term surgical outcomes of cervical dumbbell neurinomas

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

Journal of Orthopaedic Science 18 ( 1 ) 8 - 13 2013.01

ISSN 0949-2658

Study design: Retrospective case series. Objective: To evaluate our treatment strategy for cervical dumbbell neurinoma. Summary of background data: In treating cervical dumbbell neurinoma, possible difficulties include reoperation due to recurrent tumor, denervation due to nerve root resection, and postoperative spinal deformity due to extensive bony removal. Methods: We reviewed 75 cases of cervical dumbbell neurinoma that were treated surgically between 1985 and 2006. Postoperative neurological deficits, effects of surgical margins on tumor recurrence, and surgical complications were investigated retrospectively. Results: Sensory and motor deficits due to resection of specific nerve roots appeared temporarily in 33 and 23 % of all cases, and persisted in 8 and 8 % at final evaluation, respectively. Total, subtotal, and partial resection was performed in 57, 13, and 5 cases, respectively. The total resection rate was low in the tumors that had large extraforaminal components. Of the subtotally resected 13 cases, only two cases of high tumor-growth rate required re-operation or showed tumor growth. Among the five partially resected cases, re-operation was necessary in two cases 13 and 15 years later because of aggravated neurological symptoms due to tumor growth. Two patients who underwent C2 laminectomy developed kyphosis, and three patients who underwent facet joint resection and curettage of vertebral body lesions developed scoliosis. Conclusion: Total resection should be attempted for cervical dumbbell tumors. In cases where total resection was potentially of high risk, however, subtotal resection (within the capsule) was found to be a practical choice yielding favorable long-term outcome when the tumor growth rate (MIB-1 index) was low. © 2012 The Japanese Orthopaedic Association.

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Current status and perspective on regenerative medicine for spinal cord injury using iPS cell

Nakamura Masaya, Toyama Yoshiaki, Okano Hideyuki

Clinical Neurology 53 ( 11 ) 1013 - 1016 2013

ISSN 0009-918X

Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the iPS cells and reprogramming technologies in medical science. While iPS cells are expected to open new era providing enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this symposium, the pre-clinical investigations of cell therapy for SCI using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo are outlined.

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Classification of the pain nature of CRPS type 1, based on patient complaints, into neuropathic pain and nociceptive/inflammatory pain, using the McGill Pain Questionnaire

Sumitani Masahiko, Kogure Takamichi, Nakamura Masaya, Shibata Masahiko, Arito Yozu, Otake Yuko, Yamada Yoshitsugu

Journal of Anesthesia and Clinical Research 4 ( 8 ) 2013

Objectives: The precise causes of Complex Regional Pain Syndrome (CRPS) are as yet not well known. Some consider CRPS type 1 without apparent nerve injury to arise due to a prolonged inflammatory state after initial trauma and its underlying pathophysiology indicates Nociceptive/Inflammatory Pain (NocP) components. Yet others have shown clear direct evidence of nerve injury in CRPS type 1-affected limbs, and they consider CRPS type 1to be Neuropathic Pain (NeP). The McGill Pain Questionnaire (MPQ) has the potential to diagnose pain disorders as well as suggest the underlying pathophysiology. Methods: We investigated pain characteristics of 165 NeP and 66 NocP patients, by using the 78 words of the MPQ, and thereby developed a discriminant function which efficiently discriminates NocP from NeP. We then applied this function to 36 CRPS type 1 patients' complaints and classified their pain into either NocP or NeP. Results: The discriminant probability of the function was 81.0% (chi-square, p=0.24) and this function revealed 47.2% of CRPS type 1 patients' complaints were classified as NocP and 52.8% as NeP. These subgroups showed almost comparable demographic data. Considerations: Our results indicate that CRPS type 1 cannot be classified as NeP or NocP dichotomously according to pain descriptions. This raises the possibility that CRPS type 1 represents a "mixed" pain mechanism comprised of both NeP and NocP. © 2013 Sumitani M, et al.

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Recurrence of lumbar disc herniation after microendoscopic discectomy

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

Journal of Neurological Surgery, Part A: Central European Neurosurgery 74 ( 4 ) 222 - 227 2013

ISSN 2193-6315

Background Although microendoscopic discectomy (MED) is a minimally invasive surgical method for lumbar disc herniation (LDH), early postoperative recurrence may outweigh that advantage. The purpose of the present study was to retrospectively investigate the recurrence rate after MED for LDH and to determine the risk factors for recurrence in patients treated by a single surgeon. Materials and Methods The study included 344 patients who underwent MED (213 males and 131 females; mean age, 39.3 years; age range, 11-82 years; mean follow-up, 3.6 years; follow-up range, 2.0-6.5 years). The clinical outcomes were evaluated using the Japanese Orthopedic Association Score for Low Back Pain (JOA score). Recurrence factors investigated by logistic regression analysis included age; sex; level, laterality, and classified type of LDH; occupation; sports activity; and learning curve of the surgeon. Results LDH recurrence was observed in 37 patients (10.8%). It was observed at the same level in the ipsilateral side as the original LDH in 30 patients, in the contralateral side in three patients, and at a level adjacent to the original level in four patients. The mean time interval between MED and the recurrence was 16.6 months (range, 0.5-52 months). Twenty patients (54.1%) developed recurrence within 1 year after MED. Twenty-two patients (59.5%) were treated by revision surgery (MED in 20 patients and microdiscectomy in two patients), and 15 patients (40.5%) were treated conservatively. The mean JOA score of all the patients was 14.7 ± 3.5 before surgery and 26.5 ± 2.2 at the final follow-up, yielding an average recovery rate of 82.3 ± 15.7%. The recovery rate was 83.1 ± 14.8% in patients without recurrence and 75.7 ± 20.4% in patients with recurrence (p = 0.006). By logistic regression analysis, we identified migration of LDH as a significant factor related to recurrence. The patients with caudal migration of LDH had recurrence more frequently (19.0%) than those with rostral migration (12.5%) or without migration (10.2%) (p = 0.04; odds ratio, 2.0; 95% confidence interval, 1.0-3.8). Conclusion The recurrence rate and reoperation rate for LDH after MED were comparable to those of conventional discectomy. More than half of the cases of recurrence occurred at an early postoperative phase, and patients with caudally migrated LDH experienced recurrence significantly more often than those with rostrally migrated or nonmigrated LDH. ©2013 Georg Thieme Verlag KG Stuttgart, New York.

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Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury

Nishimura Soraya, Yasuda Akimasa, Iwai Hiroki, Takano Morito, Kobayashi Yoshiomi, Nori Satoshi, Tsuji Osahiko, Fujiyoshi Kanehiro, Ebise Hayao, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Molecular Brain 6 ( 1 ) 2013

Background: The transplantation of neural stem/progenitor cells (NS/PCs) at the sub-acute phase of spinal cord injury, but not at the chronic phase, can promote functional recovery. However, the reasons for this difference and whether it involves the survival and/or fate of grafted cells under these two conditions remain unclear. To address this question, NS/PC transplantation was performed after contusive spinal cord injury in adult mice at the sub-acute and chronic phases. Results: Quantitative analyses using bio-imaging, which can noninvasively detect surviving grafted cells in living animals, revealed no significant difference in the survival rate of grafted cells between the sub-acute and chronic transplantation groups. Additionally, immunohistology revealed no significant difference in the differentiation phenotypes of grafted cells between the two groups. Microarray analysis revealed no significant differences in the expression of genes encoding inflammatory cytokines or growth factors, which affect the survival and/or fate of grafted cells, in the injured spinal cord between the sub-acute and chronic phases. By contrast, the distribution of chronically grafted NS/PCs was restricted compared to NS/PCs grafted at the sub-acute phase because a more prominent glial scar located around the lesion epicenter enclosed the grafted cells. Furthermore, microarray and histological analysis revealed that the infiltration of macrophages, especially M2 macrophages, which have anti-inflammatory role, was significantly higher at the sub-acute phase than the chronic phase. Ultimately, NS/PCs that were transplanted in the sub-acute phase, but not the chronic phase, promoted functional recovery compared with the vehicle control group. Conclusions: The extent of glial scar formation and the characteristics of inflammation is the most remarkable difference in the injured spinal cord microenvironment between the sub-acute and chronic phases. To achieve functional recovery by NS/PC transplantation in cases at the chronic phase, modification of the microenvironment of the injured spinal cord focusing on glial scar formation and inflammatory phenotype should be considered. © 2013 Nishimura et al.; licensee BioMed Central Ltd.

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Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury

Takeuchi Kosei, Yoshioka Nozomu, Higa Onaga Susumu, Watanabe Yumi, Miyata Shinji, Wada Yoshino, Kudo Chika, Okada Masayasu, Ohko Kentaro, Oda Kanako, Sato Toshiya, Yokoyama Minesuke, Matsushita Natsuki, Nakamura Masaya, Okano Hideyuki, Sakimura Kenji, Kawano Hitoshi, Kitagawa Hiroshi, Igarashi Michihiro

Nature Communications 4 2013

Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration - an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes. © 2013 Macmillan Publishers Limited. All rights reserved.

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Human induced pluripotent stem (iPS) cells-derived neural stem cell bundle covered with growth factor-encapsulated amphiphilic chitosan

Kato-Negishi Midori, Onoe Hiroaki, Iwanaga Shintaroh, Kobayashi Yoshiomi, Nakamura Masaya, Okano Hideyuki, Takeuchi Shoji

1054 - 1056 2013

This paper describes human induced pluripotent stem (iPS) cell-derived neural stem cell (hiPSC-NSC) bundles covered with growth factor-encapsulated amphiphilic chitosan. The hiPSC-NSC bundle is formed by 4-12 hiPSC-NSC microfibers that are made by core-shell hydrogel microfibers encapsulating hiPSC-NSCs. The hiPSC-NSC microfibers can be cultured for over two weeks and induced to differentiate into neurons predominantly. We modified the coating material to make bundle structures that have growth factor enrichment capability (Figure 1). The coating material, amphiphilic chitosan, can release growth factors slowly for a long time, allowing hiPSC-NSCs to survive, grow and differentiate into neural lineages in the bundle structure. We believe that our hiPSC-NSC bundle would be an extremely effective tool for neural transplantation in neurodegenerative diseases such as stroke, spinal cord injury and peripheral nerve injury, because hiPSC-NSCs in the bundle structure have long-term survival ability in vivo.

Novel method for analyzing locomotor ability after spinal cord injury in rats

Shinozaki Munehisa, Yasuda Akimasa, Nori Satoshi, Saito Nobuhito, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

Neurologia Medico-Chirurgica 53 ( 12 ) 907 - 913 2013

ISSN 0470-8105

In the research for the treatment of spinal cord injury (SCI), the evaluation of motor function in model rats must be as objective, noninvasive, and ethical as possible. The maximum speed and acceleration of a mouse measured using a SCANET system were previously reported to vary significantly according to severity of SCI. In the present study, the motor performance of SCI model rats was examined with SCANET and assessed for Basso-Beattie-Bresnahan (BBB) score to determine the usefulness of the SCANET system in evaluating functional recovery after SCI. Maximum speed and acceleration within the measurement period correlated significantly with BBB scores. Furthermore, among several phased kinematic factors used in BBB scores, the capability of "plantar stepping" was associated with a drastic increase in maximum speed and acceleration after SCI. Therefore, evaluation of maximum speed and acceleration using a SCANET system is a useful method for rat models of SCI and can complement open field scoring scales. © 2013 by The Japan Neurosurgical Society.

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Pre-Evaluated Safe Human iPSC-Derived Neural Stem Cells Promote Functional Recovery after Spinal Cord Injury in Common Marmoset without Tumorigenicity

Kobayashi Yoshiomi, Okada Yohei, Itakura Go, Iwai Hiroki, Nishimura Soraya, Yasuda Akimasa, Nori Satoshi, Hikishima Keigo, Konomi Tsunehiko, Fujiyoshi Kanehiro, Tsuji Osahiko, Toyama Yoshiaki, Yamanaka Shinya, Nakamura Masaya, Okano Hideyuki

PLoS ONE 7 ( 12 ) 2012.12

Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated "safe" hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic. © 2012 Kobayashi et al.

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MRI Characterization of Paranodal Junction Failure and Related Spinal Cord Changes in Mice

Takano Morito, Hikishima Keigo, Fujiyoshi Kanehiro, Shibata Shinsuke, Yasuda Akimasa, Konomi Tsunehiko, Hayashi Akiko, Baba Hiroko, Honke Koichi, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

PLoS ONE 7 ( 12 ) 2012.12

The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure. © 2012 Takano et al.

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Novel In Vivo Imaging Analysis of an Inner Ear Drug Delivery System in Mice

Kanzaki Sho, Fujioka Masato, Yasuda Akimasa, Shibata Shinsuke, Nakamura Masaya, Okano Hirotaka James, Ogawa Kaoru, Okano Hideyuki

PLoS ONE 7 ( 12 ) 2012.12

Objective: Systemic steroid injections are used to treat idiopathic sudden-onset sensorineural hearing loss (ISSHL) and some inner ear disorders. Recent studies show that transtympanic (TT) steroid injections are effective for treating ISSHL. As in vivo monitoring of drug delivery dynamics for inner ear is lacking, its time course and dispersion of drugs is unknown. Here, we used a new in vivo imaging system to monitor drug delivery in live mice and to compare drug concentrations over time after TT and systemic injections. Methods: Luciferin delivered into the inner ears of GFAP-Luc transgenic mice reacted with luciferase in GFAP-expressing cells in the cochlear spiral ganglion, resulting in photon bioluminescence. We used the Xenogen IVIS® imaging system to measure how long photons continued to be emitted in the inner ear after TT or systemic injections of luciferin, and then compared the associated drug dynamics. Results: The response to TT and IP injections differed significantly. Photons were detected five minutes after TT injection, peaking at ~20 minutes. By contrast, photons were first detected 30 minutes after i.p. injection. TT and i.p. drug delivery time differed considerably. With TT injections, photons were detected earlier than with IP injections. Photon bioluminescence also disappeared sooner. Delivery time varied with TT injections. Conclusions: We speculate that the drug might enter the Eustachian tube from the middle ear. We conclude that inner-ear drug concentration can be maintained longer if the two injection routes are combined. As the size of luciferin differs from that of therapeutics like dexamethasone, combining drugs with luciferin may advance our understanding of in vivo drug delivery dynamics in the inner ear. © 2012 Kanzaki et al.

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Conditions for quantitative evaluation of injured spinal cord by in vivo diffusion tensor imaging and tractography

Konomi Tsunehiko, Fujiyoshi Kanehiro, Hikishima Keigo, Komaki Yuji, Tsuji Osahiko, Okano Hirotaka James, Toyama Yoshiaki, Okano Hideyuki, Nakamura Masaya

NeuroImage 63 ( 4 ) 1841 - 1853 2012.12

ISSN 1053-8119

Conventional magnetic resonance imaging (MRI) can detect hemorrhage, edema, syrinx, and spinal cord atrophy, but not axonal disruption after spinal cord injury (SCI). We previously demonstrated that diffusion tensor tractography (DTT) could depict axonal disruption after hemisection SCI in common marmosets. In the present study, to determine the relationship between DTT results and functional recovery after contusive SCI, we performed longitudinal DTT, behavioral, and histological analyses before and after contusive SCI in common marmosets. By comparing the tract fiber estimate depicted by DTT with neuronal fibers labeled with RT97 and SMI-31, anti-neurofilament antibodies, we determined the optimal fractional anisotropy (FA) threshold for fiber tracking to be 0.40. The ratio of the number of tract fiber estimates at the lesion site to the number before SCI, determined by DTT, was significantly correlated with the functional recovery after SCI. Moreover, comparison of the longitudinal pre- and post-SCI FA and axial diffusivity (λ_||) values revealed that they decreased after injury at the sites caudal to the lesion epicenter in the corticospinal tract and rostral to the lesion epicenter in the dorsal column. The FA values, then, showed partial recovery in the dorsal column. FA-value-oriented color DTT was used to represent axonal sparing or regeneration of the different tracts. These findings indicated that DTT analysis might be a versatile non-invasive tool for evaluating the axonal disruption after SCI. © 2012 Elsevier Inc.

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Efficient Derivation of Multipotent Neural Stem/Progenitor Cells from Non-Human Primate Embryonic Stem Cells

Shimada Hiroko, Okada Yohei, Ibata Keiji, Ebise Hayao, Ota Shin ichi, Tomioka Ikuo, Nomura Toshihiro, Maeda Takuji, Kohda Kazuhisa, Yuzaki Michisuke, Sasaki Erika, Nakamura Masaya, Okano Hideyuki

PLoS ONE 7 ( 11 ) 2012.11

The common marmoset (Callithrix jacchus) is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) derived from mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets. © 2012 Shimada et al.

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Comparative study of spinopelvic sagittal alignment between patients with and without degenerative spondylolisthesis

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

European Spine Journal 21 ( 11 ) 2181 - 2187 2012.11

ISSN 0940-6719

Abstract Introduction To date, few studies have focused on spinopelvic sagittal alignment as a predisposing factor for the development of degenerative spondylolisthesis (DS). The objectives of this study were to compare differences in spinopelvic sagittal alignment between patients with or without DS and to elucidate factors related to spinopelvic sagittal alignment. Materials and methods A total of 100 patients with or without DS who underwent surgery for lumbar spinal canal stenosis were assessed in this study. Fifty patients with DS (DS group) and 50 age- and gender-matched patients without DS (non-DS group) were enrolled. Spinopelvic parameters including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), L4 slope, L5 slope, thoracic kyphosis (TK), lumbar lordosis (LL) and sagittal balance were compared between the two groups. In the DS group, the percentage of vertebral slip (% slip) was also measured. Results Several spinopelvic parameters, PI, SS, L4 slope, L5 slope, TK and LL, in the DS group were significantly greater than those in the non-DS group, and PI had positive correlation with % slip (r = 0.35, p0.05). Degrees of correlations among spinopelvic parameters differed between the two groups. In the DS group, PI was more strongly correlated with SS (r = 0.82, p0.001) than with PT (r = 0.41, p0.01). In the non-DS group, PI was more strongly correlated with PT (r = 0.73, p0.001) than with SS (r = 0.38, p0.01). Conclusions Greater PI may lead to the development and the progression of vertebral slip. Different compensatory mechanisms may contribute to the maintenance of spinopelvic sagittal alignment in DS and non-DS patients. © 2012 Springer-Verlag.

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Sustained bFGF-release tubes for peripheral nerve regeneration

Takagi Takehiko, Kimura Yu, Shibata Shinsuke, Saito Harukazu, Ishii Ken, Okano Hirotaka J., Toyama Yoshiaki, Okano Hideyuki, Tabata Yasuhiko, Nakamura Masaya

Plastic and Reconstructive Surgery 130 ( 4 ) 866 - 876 2012.10

ISSN 0032-1052

BACKGROUND: Despite numerous articles on the use of artificial nerve conduits, autologous nerve transplants remain the most effective for nerve repair. To improve this technique, the authors examined conduits containing gelatin hydrogel as a carrier enabling the sustained release of basic fibroblast growth factor (bFGF). METHODS: To confirm sustained bFGF release in vivo, nerve-guide tubes containing iodine-125-labeled bFGF with or without gelatin hydrogel were implanted under the skin of mice, and the remaining radioactivity was measured. Next, a 15-mm segment of the sciatic nerve was resected and repaired with autologous nerve (group 1), a tube with gelatin hydrogel and bFGF (group 2), a tube with bFGF alone (group 3), or a tube only (group 4). Histologic and functional analyses were performed for 16 weeks after surgery. RESULTS: The radioactivity from iodine-125-labeled bFGF incorporated into gelatin hydrogel decreased more slowly than iodine-125-labeled bFGF alone. Four weeks after surgery, significantly more regenerating axons were detected in group 2 than in groups 3 and 4, but the axonal density in group 2 was lower than in group 1. Similarly, the animals in group 2 showed significantly better motor performance than those in groups 3 and 4, but worse than those in group 1. The animals in groups 1 and 2 showed significantly better sensory recovery than those in groups 3 and 4. CONCLUSIONS: The nerve-guide tube containing gelatin hydrogel and bFGF promoted axonal regeneration after peripheral nerve injury, but not as well as autologous transplants. Understanding the limitations of this technique will facilitate its improvement for clinical applications. Copyright © 2012 by the American Society of Plastic Surgeons.

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A novel multi-kinase inhibitor pazopanib suppresses growth of synovial sarcoma cells through inhibition of the PI3K-AKT pathway

Hosaka Seiichi, Horiuchi Keisuke, Yoda Masaki, Nakayama Robert, Tohmonda Takahide, Susa Michiro, Nakamura Masaya, Chiba Kazuhiro, Toyama Yoshiaki, Morioka Hideo

Journal of Orthopaedic Research 30 ( 9 ) 1493 - 1498 2012.09

ISSN 0736-0266

Synovial sarcoma is an aggressive soft tissue sarcoma with only a modest response to conventional cytotoxic agents. In the present study, we evaluated the potential antitumor effects of a novel anti-angiogenesis agent, pazopanib, against synovial sarcoma cells. We found that pazopanib directly inhibited the growth of synovial sarcoma cells by inducing G1 arrest. Multiplex analyses revealed that the PI3K-AKT pathway was highly suppressed in pazopanib-sensitive synovial sarcoma cells. Furthermore, administration of pazopanib highly suppressed the tumor growth in a xenograft model. Taken together, these results suggest pazopanib as a possible agent against synovial sarcoma and may warrant further clinical studies. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

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Serum cartilage metabolites as biomarkers of degenerative lumbar scoliosis

Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Miyamoto Takeshi, Ishii Ken, Niki Yasuo, Nakamura Masaya, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Journal of Orthopaedic Research 30 ( 8 ) 1249 - 1253 2012.08

ISSN 0736-0266

Several biomarkers have been used to evaluate osteoarthritis of the limb joints. Here we evaluated the use of serum cartilage metabolites as biomarkers for degenerative lumbar scoliosis (DLS). Fifty-two DLS patients with Cobb angle>10° were compared with 19 control patients. Serum levels of hyaluronic acid (HA), keratan sulfate (KS), cartilage oligomeric matrix protein (COMP), collagen type II cleavage (C2C), and procollagen type II C-propeptide (CPII) were measured. Serum levels of KS (DLS 1.20±0.44μg/ml vs. control 0.98±0.33μg/ml), CPII (DLS 1905.1±948.2ng/ml vs. control 1223.6±884.4ng/ml), and C2C (DLS 219.1±59.2ng/ml vs. control 177.7±71.7ng/ml) were significantly higher in DLS. There were no significant differences in the levels of HA or COMP. There was a significant positive correlation between the Cobb angle and CPII in DLS. This is the first study to evaluate the cartilage biomarkers in DLS. The results suggest DLS patients have higher levels of type II collagen synthesis and degradation, indicated by elevated serum CPII and C2C, respectively. As type II collagen is a major component of collagens in the nucleus pulposus and facet joint cartilages, its enhanced turnover may be related to the development and progression of DLS. Copyright © 2012 Orthopaedic Research Society.

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Surgical treatment of spinal extradural arachnoid cysts in the thoracolumbar spine

Funao Haruki, Nakamura Masaya, Hosogane Naobumi, Watanabe Kota, Tsuji Takashi, Ishii Ken, Kamata Michihiro, Toyama Yoshiaki, Chiba Kazuhiro, Matsumoto Morio

Neurosurgery 71 ( 2 ) 278 - 284 2012.08

ISSN 0148-396X

BACKGROUND: Because an idiopathic spinal extradural arachnoid cyst (SEAC) is rare, its optimal surgical treatment remains controversial. OBJECTIVE: To evaluate the results of surgical treatments for SEACs and to clarify features of the disease associated with poor outcomes. METHODS: Twelve patients with SEACs who underwent surgery at our hospital between 1988 and 2008 were examined retrospectively. The mean follow-up period was 4.7 years. Total resection of the cyst was performed in 7 patients and closure of the dural defect without cyst resection in 5 patients. Surgical outcomes were evaluated with regard to the duration of symptoms, the size of the cyst, and the surgical procedure used. RESULTS: Neurological recovery was observed in all patients, and there was no recurrence. Poor outcomes were observed in patients with a long duration of symptoms (>1 year, P < .01) and large cyst size (>5 vertebrae, P < .05). The surgical procedure had no significant association with the postoperative neurological recovery. However, there was a significant difference in the degree of the mean postoperative kyphotic angle between the patients treated by total resection of the cyst (9.7 degrees) and those treated by closure of the dural defect without cyst resection through selective laminectomy (2.2 degrees) (P < .01). CONCLUSION: There was no significant difference in postoperative neurological recovery between the 2 surgical procedures. However, closure of the dural defect without cyst resection was less invasive, preventing postoperative kyphotic deformity of the thoracolumbar spine. Copyright © 2012 by the Congress of Neurological Surgeons.

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