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Spinal cord injury (SCI) causes motor and sensory deficits and is currently considered an incurable disease. We have previously reported that administration of anti-High Mobility Group Box-1 monoclonal antibody (anti-HMGB1 mAb) preserved lesion area and improved locomotion recovery in mouse model of SCI. In order to further enhance the recovery, we here examined combinatorial treatment of anti-HMGB1 mAb and epothilone B (Epo B), which has been reported to promote axon regeneration. This combinatorial treatment significantly increased hindlimb movement compared with anti-HMGB1 mAb alone, although Epo B alone failed to increase functional recovery. These results are in agreement with that anti-HMGB1 mAb alone was able to decrease the lesion area spreading and increase the surviving neuron numbers around the lesion, whereas Epo B facilitated axon outgrowth only in combination with anti-HMGB1 mAb, suggesting that anti-HMGB1 mAb-dependent tissue preservation is necessary for Epo B to exhibit its therapeutic effect. Taken together, the combinatorial treatment can be considered as a novel and clinically applicable strategy for SCI.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI.

Injury to the spinal cord causes transection of axon fibers and neural cell death, resulting in disruption of the neural network and severe functional loss. Reconstruction of the damaged neural circuits was once considered to be hopeless as the adult mammalian central nervous system has very poor ability to regenerate. For this reason, there is currently no effective therapeutic treatment for spinal cord injury (SCI). However, with recent developments in stem cell research and cell culture technology, regenerative therapy using neural stem cell (NSC) transplantation has rapidly been developed, and this therapeutic strategy makes it possible to rebuild the destroyed neural circuits. In this review, we discuss the recent breakthroughs in NSC transplantation therapy for SCI. Developmental Dynamics 247:75-84, 2018. © 2017 Wiley Periodicals, Inc.

Summary Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders., Graphical Abstract, Highlights • Hypoxia-induced DNA demethylation allows hPSC-NPCs to differentiate into astrocytes • HIF1α and Notch signal activation play a critical role in this epigenetic change • RTT patient-derived astrocytes induced under hypoxia impair neuronal development, Human pluripotent stem cell-derived neural precursor cells (hNPCs) require long-term culturing to differentiate into astrocytes, retarding functional studies of human astrocytes. Nakashima and colleagues have developed a method for rapid induction of astrocytes from hNPCs cultured at low oxygen levels. Hypoxia induces epigenetic change, allowing hNPCs to differentiate into astrocytes. Their hypoxic culture should greatly accelerate research for disease-relevant astrocytes.

Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI.

Injury to the spinal cord causes transection of axon fibers and neural cell death, resulting in disruption of the neural network and severe functional loss. Reconstruction of the damaged neural circuits was once considered to be hopeless as the adult mammalian central nervous system has very poor ability to regenerate. For this reason, there is currently no effective therapeutic treatment for spinal cord injury (SCI). However, with recent developments in stem cell research and cell culture technology, regenerative therapy using neural stem cell (NSC) transplantation has rapidly been developed, and this therapeutic strategy makes it possible to rebuild the destroyed neural circuits. In this review, we discuss the recent breakthroughs in NSC transplantation therapy for SCI. Developmental Dynamics 247:75-84, 2018. © 2017 Wiley Periodicals, Inc.

Although the central nervous system is considered a comparatively static tissue with limited cell turnover, cells with stem cell properties have been isolated from most neural tissues. The spinal cord ependymal cells show neural stem cell potential in vitro and in vivo in injured spinal cord. However, very little is known regarding the ependymal niche in the mouse spinal cord. We previously reported that a secreted factor, chick Akhirin, is expressed in the ciliary marginal zone of the eye, where it works as a heterophilic cell-adhesion molecule. Here, we describe a new crucial function for mouse Akhirin (M-AKH) in regulating the proliferation and differentiation of progenitors in the mouse spinal cord. During embryonic spinal cord development, M-AKH is transiently expressed in the central canal ependymal cells, which possess latent neural stem cell properties. Targeted inactivation of the AKH gene in mice causes a reduction in the size of the spinal cord and decreases BrdU incorporation in the spinal cord. Remarkably, the expression patterns of ependymal niche molecules in AKH knockout (AKH−/−) mice are different from those of AKH+/+, both in vitro and in vivo. Furthermore, we provide evidence that AKH expression in the central canal is rapidly upregulated in the injured spinal cord. Taken together, these results indicate that M-AKH plays a crucial role in mouse spinal cord formation by regulating the ependymal niche in the central canal. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 494–504, 2015

腓骨近位部に発生した軟骨粘液線維腫の1例を経験したので報告した．症例は16歳男性．右膝打撲後より疼痛が出現．近医受診し，単純X線上右腓骨頭に境界明瞭な骨透亮像を指摘され当科紹介受診．単純X線では骨皮質の膨隆と菲薄化を認め，髄内には隔壁構造を伴った骨透亮像を認めた．MRIではT1WIで筋と等信号，T2WIで高信号，不均一な造影効果を伴う骨内腫瘤を認めた．術中迅速病理診断を行い軟骨粘液線維腫の診断を得たため，病巣掻爬及び人工骨移植を行った．軟骨粘液線維腫は長管骨，特に脛骨の骨幹端部に好発する比較的稀な良性骨腫瘍であるが，腓骨近位部での発生の報告は少ない．掻爬での再発率は20％前後と比較的高い再発率の報告が多く，本症例においても今後の注意深い経過観察が必要と思われる．腓骨近位部における骨腫瘍の鑑別として，稀ではあるが軟骨粘液線維腫も念頭に置く必要があると思われた．

Although the central nervous system is considered a comparatively static tissue with limited cell turnover, cells with stem cell properties have been isolated from most neural tissues. The spinal cord ependymal cells show neural stem cell potential in vitro and in vivo in injured spinal cord. However, very little is known regarding the ependymal niche in the mouse spinal cord. We previously reported that a secreted factor, chick Akhirin, is expressed in the ciliary marginal zone of the eye, where it works as a heterophilic cell-adhesion molecule. Here, we describe a new crucial function for mouse Akhirin (M-AKH) in regulating the proliferation and differentiation of progenitors in the mouse spinal cord. During embryonic spinal cord development, M-AKH is transiently expressed in the central canal ependymal cells, which possess latent neural stem cell properties. Targeted inactivation of the AKH gene in mice causes a reduction in the size of the spinal cord and decreases BrdU incorporation in the spinal cord. Remarkably, the expression patterns of ependymal niche molecules in AKH knockout (AKH-/-) mice are different from those of AKH+/+, both in vitro and in vivo. Furthermore, we provide evidence that AKH expression in the central canal is rapidly upregulated in the injured spinal cord. Taken together, these results indicate that M-AKH plays a crucial role in mouse spinal cord formation by regulating the ependymal niche in the central canal.

カフェイン併用化学療法にて肺転移巣が著明に縮小した症例を経験したので報告する．症例は17歳男性，脛骨近位例．CDDP+DXRにて術前補助化学療法を行ったが肺転移が出現．IFO＋VP-16に変更し近位脛骨置換術を施行したが肺転移は増大傾向であった．その後5回の肺部分切除術を施行したが再発したため，IFO＋VP-16にカフェインを併用し病巣の著明な縮小を認めた．最終的に肺転移出現後46か月で腫瘍死となった．近年，悪性骨軟部腫瘍に対するカフェイン併用化学療法の有効性が報告されている．本症例では初期治療においてIFO＋VP-16で肺転移をコントロールし得なかったが，カフェインを併用したことで著明な肺転移巣の縮小と呼吸器症状の改善による延命効果が得られた．カフェイン併用により殺腫瘍効果が増強されたものと思われる．

悪性軟部腫瘍肺転移例28例（男性18例，女性10例）について検討した．年齢18～91歳（平均49.6歳），経過観察期間2か月～12年（平均33か月），組織型はMFH 8例，滑膜肉腫7例，平滑筋肉腫6例，MPNST 3例，脂肪肉腫2例，円形細胞肉腫2例であった．肺転移出現時期は初診時8例，治療中4例，治療後16例であり，肺転移に対する手術は8例（29％）に行われていた．生命予後はNED：2例，AWD 5例，DOD 21例であった．経過観察開始から1年／2年／5年の累積生存率は71.3％／44.9％／19.1％（中央値22か月）であった．組織別では滑膜肉腫が良好で，平滑筋肉腫が続き，他は不良であった．治療別では手術＋化学療法が良く，化学療法のみが続き，治療なしは不良であった．転移巣切除可能例では予後が良好であり可能な限り積極的に外科的切除を行うことが予後の改善につながると考えられた．

Three-dimensional (3D) open-field gait analysis of mice is an essential procedure in genetic and nerve regeneration research. Existing gait analysis systems are generally expensive and may interfere with the natural behaviors of mice because of optical markers and transparent floors. In contrast, the proposed system captures the subjects shape from beneath using a low-cost infrared depth sensor (Microsoft Kinect) and an opaque infrared pass filter. This means that we can track footprints and 3D paw-tip positions without optical markers or a transparent floor, thereby preventing any behavioral changes. Our experimental results suggest with healthy mice that they are more active on opaque floors and spend more time in the center of the open-field, when compared with transparent floors. The proposed system detected footprints with a comparable performance to existing systems, and precisely tracked the 3D paw-tip positions in the depth image coordinates.