J Neurosci Res. 2014 Jul;92(7):856-69. doi: 10.1002/jnr.23368.
Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)- or FMS-like tyrosine kinase 3 (flt3)-activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM-derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter-1 (GLT-1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor-α and interleukin-1β were suppressed and the neuroprotective molecule insulin-like growth factor-1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF-activated BM cells as a potential new therapeutic agent for the treatment of ALS.
肌萎缩侧索硬化症（ALS）是一种与运动神经元死亡相关的进行性疾病。已经在 ALS 动物模型中测试了几种实验性治疗方法，包括使用造血或神经元干细胞的细胞治疗，但治疗效果有限。在这里，我们使用了一种新的治疗策略，即用干细胞因子（SCF）或 FMS 样酪氨酸激酶 3（flt3）激活的骨髓（BM）细胞进行骨髓移植（BMT）来治疗 hSOD1（G93A）转基因小鼠。与未激活的 BM 细胞（单独 BMT 组）相比，SCF 组的运动功能和存活率有更大的改善，尽管 flt3 组没有改善。此外，与单独 BMT 组相比，更多表达小胶质细胞标志物 Iba1 的 BM 来源细胞迁移到受者小鼠的脊髓中。此外，在 SCF 激活后，但在 flt3 激活或不激活后，迁移的小胶质细胞表达谷氨酸转运体-1（GLT-1）。在 SCF 组的脊髓中，与未经治疗的 hSOD1（G93A）转基因小鼠相比，肿瘤坏死因子-α和白细胞介素-1β等炎症细胞因子受到抑制，神经保护分子胰岛素样生长因子-1增加。因此，SCF 激活改变了迁移供体 BM 细胞的特征，从而产生了神经保护作用。这些研究确定了 SCF 激活的 BM 细胞作为治疗 ALS 的一种潜在新治疗剂。
