Felsenstein Medical Research Center, Department of Neurology, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Exp Neurol. 2012 Apr;234(2):417-27. doi: 10.1016/j.expneurol.2011.12.045. Epub 2012 Jan 20.
Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.
亨廷顿病（HD）是一种遗传性、进行性的、最终致命的神经退行性疾病。兴奋性毒性和神经营养因子（NTFs）的减少可能在 HD 的发病机制中发挥作用。最近，我们开发了一种方案，可诱导成人骨髓来源的间充质干细胞（MSCs）成为 NTF 分泌细胞（NTF(+)细胞）。将这些细胞移植到纹状体代表了一种有前途的自体治疗方法，可将 NTF 递送到受损区域。在这里，我们使用喹啉酸（QA）兴奋性毒性大鼠模型评估了 NTF(+)细胞的疗效。我们发现，在 QA 注射后移植到大鼠大脑中的 NTF(+)细胞能够存活（6 周后为 19%），保持其 NTF 分泌表型，并显著减少与 QA 损伤相关的纹状体体积变化。此外，用 NTF(+)细胞治疗的 QA 注射大鼠表现出改善的行为；即，与用 PBS 处理的 QA 注射大鼠相比，进行的阿扑吗啡诱导旋转次数减少了 80%。重要的是，我们发现来自 HD 患者的 MSCs 可以被诱导成为 NTF(+)细胞，并发挥类似来自健康供体的 NTF(+)细胞的有效作用。据我们所知，这是第一项将来自遗传性疾病的成人骨髓来源的间充质干细胞移植到动物模型中并证明治疗效果的研究。我们使用 MRI 证明，在体内，用 PBS 处理的 QA 注射纹状体在病变区域的 T(2)值随时间增加，而用 NTF(+)细胞治疗的 QA 注射大鼠的等效区域的 T(2)值降低。我们得出结论，NTF 细胞治疗可作为治疗 HD 的新方法。
