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Grant amount：\16900000 （ Direct Cost: \13000000 、 Indirect Cost：\3900000 ）

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Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

超高齢化社会を迎える日本にとって、老化メカニズムを解明し、健康寿命を延長することは最重要課題である。これまでの老化研究では、老化・寿命制御に重要な役割を果たす制御因子・シグナル伝達系の特定がなされてきたが、これまでのところ、健康寿命の延長をもたらし、認知・運動機能を維持・向上するための治療法には結びついていない。一方、我々は、健康な若年ラットから採取した間葉系幹細胞（ｍｅｓｅｎｃｈｙｍａｌ ｓｔｅｍ ｃｅｌｌｓ：ＭＳＣｓ）を、複数の神経疾患モデル動物に対し、経静脈的に投与した結果、寿命が延長する可能性を見出した。成体の体性幹細胞であるＭＳＣｓは、主に骨髄に存在し、骨髄から末梢循環へ移行し、臓器の新陳代謝・機能維持に関わると同時に、損傷時における治癒プロセスにも貢献している。すなわち、ＭＳＣｓは、生体全体の恒常性維持（ホメオスターシス）と自己治癒力に大きく貢献している細胞との認識が広まっており、既に複数の疾患をターゲットとした臨床応用に期待が高まっている。我々は、老化により生体内のＭＳＣｓが機能低下を起こすことが、個体の老化の原因となっていると考えている。本研究では、ラットから採取したＭＳＣｓの投与によって得られる健康寿命延伸による認知・運動機能の維持・改善、などの“抗加齢効果”をもたらすメカニズムを解明し、成体の持つ生命を維持する能力を発揮させるための治療法へ展開することを目的としている。以上のように、補助金は適切に使用している。

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Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

Neurofunctional recovery in spinal cord injury following intravenous infusion of Mesenchymal stem cells has been reported. It is one of the most important mechanisms of functional improvement that remote responses occur in the brain as well as in the injured spinal cord. In this study, we performed MRI analysis after MSC administration in spinal cord injury cases, as well as histological and MRI analysis in animal models, and demonstrated the reorganization of neural circuits.

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

We investigated the therapeutic effects and mechanisms of repeated intravenous infusion of mesenchymal stem cells (MSCs) to a rat model with chronic spinal cord injury (SCI). Chronic SCI rats were randomized and infused with vehicle (Vehicle), single MSC injection (MSC-1), single high dose injection (HD-MSC) at week 6, or repeatedly injections of MSCs at 6, 7, and 8 weeks (MSC-3) after SCI induction. Behavioral analysis using BBB score, histological analysis evaluating remyelinated axons and sprouting of CST fibers and raphespinal fiber growth, and ex vivo DTI analysis. In behavioral, histological, and ex vivo DTI analyses, all MSC-treated groups showed improvement compared to the vehicle group, but the MSC-3 showed the most improvement. There was no difference in improvement between the MSC-1 and HD-MSC groups.The same trend was observed for pain suppression.The results indicated that repeated dosing may be more effective when MSC therapy is applied to patients with chronic SCI.

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Grant amount：\17290000 （ Direct Cost: \13300000 、 Indirect Cost：\3990000 ）

Intravenous administration of MSCs in spinal cord injury promotes functional recovery through a multistep process. This includes neuroprotection, blood-spinal cord barrier stabilization, axon sprouting and regeneration, remyelination, and synaptogenesis. We aimed to investigate neuronal circuit reconstruction after MSC treatment using axonal tracers. By visualizing axon distribution, we observed increased communication between corticospinal tract and lateral funiculus axons both above and below the injury site. This enhanced axonal network may contribute to functional recovery by providing significant input below the injury.

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

We have previously reported that intravenous administration of MSCs to a spinal cord injury model can restore motor function. We also reported that genetic analysis of the cortical motor cortex on the third day of transplantation, when motor function was restored, revealed changes in the expression levels of several genes, many of which are involved in nerve regeneration and increased plasticity (Oshigiri et al.,2019). Therefore, in this study, we expanded on previous studies and performed a comprehensive genetic analysis using an integrated database to analyze the profile of genes involved in the expression of the therapeutic effect.

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

We investigated the mechanism of treatment of experimental cerebral infarction by the combination of rehabilitation and intravenous administration of bone marrow mesenchymal stem cells (MSCs) . The effect of the treatment under each condition was examined. The results showed that there were differences in the therapeutic effects at each exercise level. In the future, it will be necessary to continue to examine the neuroplasticity of combined rehabilitation, and to conduct further research to establish a rehabilitation protocol that maximizes the therapeutic effect.

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Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

In this study, we demonstrated that the therapeutic efficacy of intravenous infusion of mesenchymal stem cells (MSCs) was enhanced via induced neural plasticity in the whole brain using MRI diffusion tensor imaging. We also showed that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. Administration of MSCs is associated with the promotion of whole interhemispheric connectivity through the corpus callosum even in the chronic phase of cerebral infarction.

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Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

In this study, we demonstrated that intravenous infusion of MSCs increased the survival rate in rat models of spontaneously hypertensive (stroke-prone) in which organs including kidney, brain, heart, and liver are damaged during aging due to spontaneous hypertension. Intravenous infusion of MSC may extend lifespan in addition to preventing the deterioration of motor and cognitive functions in the animal model.

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Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

The reorganization of neural circuits in the brain after spinal cord injury has been previously reported using MRI diffusion tensor imaging and other techniques, but there are few reports using detailed neuroanatomical methods. The purpose of this study was to analyze in detail the reorganization of neural circuits in the brain after spinal cord injury using adeno-associated virus (AAV), which is known as a progressive neural tracer.
AAV-8 carrying the CAG promoter was found to have high efficiency of transduction, adaptive tracking, and cell-selective labeling in the brain. Furthermore, analysis of the brain after spinal cord injury using the same vector suggested that neural circuit reconstruction had occurred.

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Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

We demonstrated that an intravenous infusion of MSCs delay disease progression through the preservation of BSCB function and increased expression of a neurotrophic factor, neurturin, in SOD1G93A ALS rats. The MSC group exhibited reduced deterioration of locomotor activity compared to the vehicle group, which displayed progressive deterioration of hind limb function. We observed the protection of motor neuron loss and preservation of microvasculature in the MSC group. Neurturin expression levels were significantly higher in the MSC group. Thus, restoration of the BSCB and the protection of motor neurons might be contributing mechanisms to delay disease progression in SOD1G93A ALS rats. We also showed that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion.

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Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

Neurofunctional recovery in spinal cord injury following intravenous infusion of Mesenchymal stem cells has been reported. It is one of the most important mechanisms of functional improvement that remote responses occur in the brain as well as in the injured spinal cord. Therefore, we performed MRI analysis after MSC administration for spinal cord injury in patients and animal experimental models, and histological analysis for animal models at the same time, and clarified that neural circuit rearrangement occurred.

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Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

Recent studies has demonstrated that remote responses in the brain, as well as local responses in the injured spinal cord, can be occurred following spinal cord injury (SCI). Intravenous infusion of mesenchymal stem cells (MSCs) has been shown to elicit functional recovery in SCI through local mechanisms. We studied brain response that might be associated with the functional improvements induced by the infused MSCs following SCI. Genomewide RNA profiling was conducted in the motor cortex of SCI rats at 3 days post infusion. Then, qRT-PCR revealed that the ‘‘behaviorally-associated differentially expressed genes (DEGs)’’ were identified by the Pearson’s correlation analysis with the behavioral function, suggesting that these genes may be related to the functional recovery after infused MSCs. These results suggested that the infused MSCs alter the gene expression signature in the brain and that these expression changes may contribute to the improved function.

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