Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.

中文翻译：

---

诱导神经干细胞（iNSC）移植到慢性脱髓鞘的in体中可改善运动功能障碍。

多发性硬化症（MS）会因发炎，脱髓鞘和神经变性而导致神经功能障碍。免疫抑制疗法可以改变病程，但不能有效地促进髓鞘再生或预防长期的神经变性。作为缓解慢性病理的一种新方法，我们测试了小鼠诱导的神经干细胞（iNSCs）向成年小鼠的慢性脱髓鞘my体（CC）的移植。喂食0.3％铜酮12周的雄性C57BL / 6小鼠表现出CC萎缩，慢性脱髓鞘，星形胶质增生和小胶质细胞活化。终止铜酮后，同基因iNSCs移植到CC中，并于2周后灌注进行神经病理学检查。用于磁化传递比（MTR）的磁共振成像（MRI）序列，扩散加权成像（T2），和扩散张量成像（DTI）量化了iNSC移植前后活小鼠的CC病理。每种MRI技术都检测到进行性CC病理。接受iNSC的小鼠的DTI径向扩散率正常化，成像后星形胶质变减少。参与CC的一项运动技能任务是失步车轮行驶，这证明了铜酮脱髓鞘导致的功能缺陷。iNSCs的移植导致跑步速度明显恢复。车轮行驶后的神经病理学表明，iNSC移植物显着增加了宿主少突胶质细胞和增殖性少突胶质细胞祖细胞，同时调节了轴突损伤。移植的iNSCs沿星形胶质细胞和少突胶质细胞谱系分化，没有髓鞘形成，许多仍然是神经干细胞。我们的发现证明了神经影像学和功能评估在慢性脱髓鞘期间的临床前干预试验中的适用性，并检测了iNSC移植后的功能改善。将成纤维细胞直接重编程为iNSC有助于将来向外源性自体细胞疗法的转化。