Department of Neuroscience, University Medical Centre Groningen, Groningen, The Netherlands.
Cell Transplant. 2012;21(9):1883-97. doi: 10.3727/096368911X637443. Epub 2012 Mar 28.
In multiple sclerosis (MS), a chronic inflammatory relapsing demyelinating disease, failure to control or repair damage leads to progressive neurological dysfunction and neurodegeneration. Implantation of neural stem cells (NSCs) has been shown to promote repair and functional recovery in the acute experimental autoimmune encephalomyelitis (EAE) animal model for MS; the major therapeutic mechanism of these NSCs appeared to be immune regulation. In the present study, we examined the efficacy of intraventricularly injected NSCs in chronic relapsing experimental autoimmune encephalomyelitis (CREAE), the animal disease model that is widely accepted to mimic most closely recurrent inflammatory demyelination lesions as observed in relapsing-remitting MS. In addition, we assessed whether priming these NSCs to become oligodendrocyte precursor cells (OPCs) by transient overexpression of Olig2 would further promote functional recovery, for example, by contributing to actual remyelination. Upon injection at the onset of the acute phase or the relapse phase of CREAE, NSCs as well as Olig2-NSCs directly migrated toward active lesions in the spinal cord as visualized by in vivo bioluminescence and biofluorescence imaging, and once in the spinal cord, the majority of Olig2-NSCs, in contrast to NSCs, differentiated into OPCs. The survival of Olig2-NSCs was significantly higher than that of injected control NSCs, which remained undifferentiated. Nevertheless, both Olig2-NSCs and NSC significantly reduced the clinical signs of acute and relapsing disease and, in case of Olig2-NSCs, even completely abrogated relapsing disease when administered early after onset of acute disease. We provide the first evidence that NSCs and in particular NSC-derived OPCs (Olig2-NSCs) ameliorate established chronic relapsing EAE in mice. Our experimental data in established neurological disease in mice indicate that such therapy may be effective in relapsing-remitting MS preventing chronic progressive disease.
在多发性硬化症（MS）中，一种慢性炎症性复发性脱髓鞘疾病，由于无法控制或修复损伤，导致进行性神经功能障碍和神经退行性变。研究表明，植入神经干细胞（NSCs）可促进多发性硬化症实验性自身免疫性脑脊髓炎（EAE）动物模型的急性修复和功能恢复；这些 NSCs 的主要治疗机制似乎是免疫调节。在本研究中，我们检查了脑室注射 NSCs 在慢性复发性实验性自身免疫性脑脊髓炎（CREAE）中的疗效，该动物疾病模型被广泛认为最能模拟复发性多发性硬化症中观察到的复发性炎症性脱髓鞘病变。此外，我们评估了通过短暂过表达 Olig2 将这些 NSCs 诱导为少突胶质前体细胞（OPCs）是否会进一步促进功能恢复，例如，通过有助于实际的髓鞘再生。在 CREAE 的急性或复发阶段开始时注射 NSCs 和 Olig2-NSCs 后，通过体内生物发光和生物荧光成像直接迁移到脊髓中的活性病变部位，并且一旦进入脊髓，大多数 Olig2-NSCs 与 NSCs 不同，分化为 OPCs。与注射的未分化对照 NSCs 相比，Olig2-NSCs 的存活率显著更高。然而，Olig2-NSCs 和 NSCs 均显著减轻了急性和复发疾病的临床症状，并且在早期急性疾病发作后给予 Olig2-NSCs 时甚至完全消除了复发疾病。我们提供了第一个证据，证明 NSCs 特别是 NSC 衍生的少突胶质细胞前体细胞（Olig2-NSCs）可改善小鼠慢性复发性 EAE。我们在小鼠已建立的神经疾病中的实验数据表明，这种治疗方法可能对复发性缓解型多发性硬化症预防慢性进行性疾病有效。
