Kim Hyun Sook, Jeon Iksoo, Noh Jeong-Eun, Lee Hyunseung, Hong Kwan Soo, Lee Nayeon, Pei Zhong, Song Jihwan
Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea.
CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
Exp Neurobiol. 2020 Apr 30;29(2):130-137. doi: 10.5607/en20011.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by abnormally expanded CAG repeats in the gene. The gene mutation leads to the progressive degeneration of striatal GABAergic medium spiny neurons (MSN) and reduces the level of brain-derived neurotrophic factor (BDNF) in HD patient's brain. BDNF is an essential neurotrophic factor for the cortico-striatal synaptic activity and the survival of GABAergic neurons. In this study, we transplanted BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) into the contra-lateral side of unilateral quinolinic acid (QA)-lesioned striatum of HD rat model. The results of transplantation were monitored using various behavioral tests, 4.7 T animal magnetic resonance imaging (MRI) and immunohistochemical staining. We observed that the QA-lesioned rats receiving HB1.F3.BDNF cells exhibited significant behavioral improvements in the stepping, rotarod and apomorphine-induced rotation tests. Interestingly, contralaterally transplanted cells were migrated to the QA-lesioned striatum and the size of lateral ventricle was reduced. Histological analyses further revealed that the transplanted cells, which had migrated to the QA lesion site, were differentiated into the cells of GABAergic, MSN-type neurons expressing DARPP-32, and neural networks were established between the transplanted cells and the host brain, as revealed by retrograde tracing. Finally, there was a significant reduction of inflammatory response in HB1.F3.BDNF-transplanted HD animal model, compared with vehicle-transplanted group. Taken together, these results suggest that HB1.F3.BDNF can be an effective therapeutic strategy to treat HD patients in the future.
亨廷顿舞蹈症（HD）是一种由该基因中异常扩增的CAG重复序列引起的常染色体显性遗传神经退行性疾病。该基因突变导致纹状体γ-氨基丁酸能中等棘状神经元（MSN）逐渐退化，并降低HD患者大脑中脑源性神经营养因子（BDNF）的水平。BDNF是皮质-纹状体突触活动和γ-氨基丁酸能神经元存活所必需的神经营养因子。在本研究中，我们将过表达BDNF的人神经干细胞（HB1.F3.BDNF）移植到HD大鼠模型单侧喹啉酸（QA）损伤纹状体的对侧。使用各种行为测试、4.7T动物磁共振成像（MRI）和免疫组织化学染色监测移植结果。我们观察到，接受HB1.F3.BDNF细胞移植的QA损伤大鼠在步幅、转棒和阿扑吗啡诱导旋转测试中表现出显著的行为改善。有趣的是，对侧移植的细胞迁移到QA损伤的纹状体，侧脑室大小减小。组织学分析进一步显示，迁移到QA损伤部位的移植细胞分化为表达DARPP-32的γ-氨基丁酸能、MSN型神经元细胞，逆行追踪显示移植细胞与宿主脑之间建立了神经网络。最后，与载体移植组相比，HB1.F3.BDNF移植的HD动物模型中的炎症反应显著降低。综上所述，这些结果表明HB1.F3.BDNF可能是未来治疗HD患者的一种有效治疗策略。
