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首页> 外文期刊>Stem Cells >Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid β ameliorates Alzheimer's disease in mice by recruiting bone marrow-induced microglia immune responses
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Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid β ameliorates Alzheimer's disease in mice by recruiting bone marrow-induced microglia immune responses

机译：源自骨髓间充质干细胞的可溶性CCL5受到淀粉样β的激活，可通过募集骨髓诱导的小胶质细胞免疫应答来改善小鼠阿尔茨海默氏病

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Microglia have the ability to eliminate amyloid β (Aβ) by a cell-specific phagocytic mechanism, and bone marrow (BM) stem cells have shown a beneficial effect through endogenous microglia activation in the brains of Alzheimer's disease (AD) mice. However, the mechanisms underlying BM-induced activation of microglia have not been resolved. Here we show that BM-derived mesenchymal stem cells (MSCs) induced the migration of microglia when exposed to Aβ in vitro. Cytokine array analysis of the BM-MSC media obtained after stimulation by Aβ further revealed elevated release of the chemoattractive factor, CCL5. We also observed that CCL5 was increased when BM-MSCs were transplanted into the brains of Aβ-deposited AD mice, but not normal mice. Interestingly, alternative activation of microglia in AD mice was associated with elevated CCL5 expression following intracerebral BM-MSC transplantation. Furthermore, by generating an AD-green fluorescent protein chimeric mouse, we ascertained that endogenous BM cells, recruited into the brain by CCL5, induced microglial activation. Additionally, we observed that neprilysin and interleukin-4 derived from the alternative microglia were associated with a reduction in Aβ deposition and memory impairment in AD mice. These results suggest that the beneficial effects observed in AD mice after intracerebral SC transplantation may be explained by alternative microglia activation. The recruitment of the alternative microglia into the brain is driven by CCL5 secretion from the transplanted BM-MSCs, which itself is induced by Aβ deposition in the AD brain.
机译：小胶质细胞具有通过细胞特异性吞噬机制消除淀粉样蛋白β（Aβ）的能力，并且骨髓（BM）干细胞通过内源性小胶质细胞激活阿尔茨海默氏病（AD）小鼠的大脑显示出有益的作用。但是，BM诱导的小胶质细胞激活的机制尚未解决。在这里，我们显示了BM来源的间充质干细胞（MSC）在体外暴露于Aβ时会诱导小胶质细胞的迁移。对Aβ刺激后获得的BM-MSC培养基进行细胞因子阵列分析，进一步揭示了趋化因子CCL5的释放升高。我们还观察到，当将BM-MSCs移植到Aβ沉积的AD小鼠的大脑中而不是正常小鼠的大脑中时，CCL5会增加。有趣的是，脑内BM-MSC移植后，AD小鼠小胶质细胞的替代激活与CCL5表达升高有关。此外，通过产生AD绿色荧光蛋白嵌合小鼠，我们确定了由CCL5募集入大脑的内源性BM细胞诱导了小胶质细胞的激活。另外，我们观察到来自替代小胶质细胞的中性溶素和白细胞介素-4与AD小鼠Aβ沉积和记忆障碍的减少有关。这些结果表明，大脑SC移植后在AD小鼠中观察到的有益作用可能是由其他小胶质细胞激活引起的。替代性小胶质细胞向大脑的募集是由移植的BM-MSC分泌的CCL5分泌驱动的，而这本身是由AD脑中Aβ沉积诱导的。

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