Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea.
Stem Cells. 2011 Jul;29(7):1075-89. doi: 10.1002/stem.659.
Transplantation of bone marrow-derived stem cells (BMSCs) has been suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines. Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor (G-CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1α (SDF-1α) on endogenous BM-derived hematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice received an intracerebral injection with SDF-1α to induce migration of mobilized BM-HPCs into brain. We found that the memory deficit in the AD mice was significantly improved by these treatments, but amyloid β deposition was unchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1-green fluorescent protein (GFP) chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally, increased hippocampal neurogenesis and improved memory was observed in mice receiving combined G-CSF/AMD3100 and SDF-1α, but not in controls or animals receiving each treatment alone. These results suggest that SDF-1α is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized by G-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants further investigation as a potential therapeutic option for the treatment of AD patients in the future.
骨髓源性干细胞（BMSCs）移植已被提议作为一种预防神经退行性疾病的潜在治疗方法，但由于植入、潜在毒性和其他因素的问题，该方法仍然存在问题。另一种策略是通过全身给予生长因子或趋化因子将内源性 BMSCs 募集到受损部位。因此，本研究旨在探讨粒细胞集落刺激因子（G-CSF）/AMD3100（CXCR4 拮抗剂）和基质细胞衍生因子-1α（SDF-1α）治疗对阿尔茨海默病（AD）小鼠模型内源性 BM 来源造血祖细胞（BM-HPC）募集到大脑的影响。为了动员 BM-HPC，将 G-CSF 腹腔内注射，并通过 AMD3100 增强。同时，这些小鼠接受脑内注射 SDF-1α，以诱导动员的 BM-HPC 迁移到大脑。我们发现，这些治疗方法显著改善了 AD 小鼠的记忆缺陷，但淀粉样β沉积没有改变。有趣的是，小胶质细胞的激活增加，表现为小胶质细胞的替代激活向神经保护表型。此外，通过生成淀粉样前体蛋白/早老素 1-绿色荧光蛋白（GFP）嵌合小鼠，我们确定了在大脑中鉴定出的 GFP 阳性小胶质细胞是 BM 来源的。此外，在接受 G-CSF/AMD3100 和 SDF-1α 联合治疗的小鼠中观察到海马神经发生增加和记忆改善，但在对照或单独接受每种治疗的动物中没有观察到。这些结果表明，SDF-1α 是一种有效的佐剂，可诱导 G-CSF/AMD3100 动员的内源性 BM-HPC 向大脑迁移，并且两者可以协同作用产生治疗效果。这种方法值得进一步研究，作为未来治疗 AD 患者的潜在治疗选择。
