Sadan Ofer, Bahat-Stromza Merav, Barhum Yael, Levy Yossef S, Pisnevsky Anat, Peretz Hagit, Ilan Avihay Bar, Bulvik Shlomo, Shemesh Noam, Krepel Dana, Cohen Yoram, Melamed Eldad, Offen Daniel
Laboratory of Neurosciences, Felsenstein Medical Research Center, Department of Neurology, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Stem Cells Dev. 2009 Oct;18(8):1179-90. doi: 10.1089/scd.2008.0411.
Stem cell-based therapy is a promising treatment for neurodegenerative diseases. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells (MSC) into neurotrophic factors- secreting cells (NTF-SC), thus combining stem cell-based therapy with the NTF-based neuroprotection. These cells produce and secrete factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor. Conditioned medium of the NTF-SC that was applied to a neuroblastoma cell line (SH-SY5Y) 1 h before exposure to the neurotoxin 6-hydroxydopamine (6-OHDA) demonstrated marked protection. An efficacy study was conducted on the 6-OHDA-induced lesion, a rat model of Parkinson's disease. The cells, either MSC or NTF-SC, were transplanted on the day of 6-OHDA administration and amphetamine-induced rotations were measured as a primary behavior index. We demonstrated that when transplanted posterior to the 6-OHDA lesion, the NTF-SC ameliorated amphetamine-induced rotations by 45%. HPLC analysis demonstrated that 6-OHDA induced dopamine depletion to a level of 21% compared to the untreated striatum. NTF-SC inhibited dopamine depletion to a level of 72% of the contralateral striatum. Moreover, an MRI study conducted with iron-labeled cells, followed by histological verification, revealed that the engrafted cells migrated toward the lesion. In a histological assessment, we found that the cells induced regeneration in the damaged striatal dopaminergic nerve terminal network. We therefore conclude that the induced MSC have a therapeutic potential for neurodegenerative processes and diseases, both by the NTFs secretion and by the migratory trait toward the diseased tissue.
基于干细胞的疗法是治疗神经退行性疾病的一种很有前景的方法。在我们实验室，已开发出一种新方案，可将骨髓间充质干细胞（MSC）诱导为分泌神经营养因子的细胞（NTF-SC），从而将基于干细胞的疗法与基于NTF的神经保护相结合。这些细胞产生并分泌诸如脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子等因子。在暴露于神经毒素6-羟基多巴胺（6-OHDA）前1小时，将NTF-SC的条件培养基应用于神经母细胞瘤细胞系（SH-SY5Y），显示出显著的保护作用。对6-OHDA诱导的损伤（一种帕金森病大鼠模型）进行了疗效研究。在给予6-OHDA的当天移植细胞，无论是MSC还是NTF-SC，并将苯丙胺诱导的旋转作为主要行为指标进行测量。我们证明，当在6-OHDA损伤后移植时，NTF-SC可使苯丙胺诱导的旋转减少45%。高效液相色谱分析表明，与未处理的纹状体相比，6-OHDA使多巴胺耗竭至21%的水平。NTF-SC抑制多巴胺耗竭至对侧纹状体72%的水平。此外，一项对铁标记细胞进行的MRI研究，随后进行组织学验证，结果显示移植的细胞向损伤部位迁移。在组织学评估中，我们发现这些细胞诱导受损纹状体多巴胺能神经终末网络再生。因此，我们得出结论，诱导的MSC通过分泌NTF以及向患病组织的迁移特性，对神经退行性过程和疾病具有治疗潜力。
