Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model.
Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model.
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间充质干细胞衍生的细胞外囊泡在临床前小鼠模型中改善阿尔茨海默氏病的表型。
DOI：
10.7150/thno.62069
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Meckes DG Jr
中科院分区：
文献类型：
--
作者：
Cone AS;Yuan X;Sun L;Duke LC;Vreones MP;Carrier AN;Kenyon SM;Carver SR;Benthem SD;Stimmell AC;Moseley SC;Hike D;Grant SC;Wilber AA;Olcese JM;Meckes DG Jr
阿尔茨海默病（AD）是一种不可逆的神经退行性疾病，影响全球超过4400万人。尽管疾病负担很高，但对患有AD的人没有有效的治疗方法。间充质干细胞（MSC）是多能的基质细胞，由于其治疗潜力而被广泛研究。然而，已经发现细胞的施用具有许多限制。最近，来源于MSC的细胞外囊泡（EV）已被研究作为治疗候选物，因为它们表现出与宿主人MSC相似的免疫保护和免疫调节能力。研究方法：为了测试MSC EV的潜在治疗效果，使人骨髓来源的MSC在三维（3D）细胞培养物中生长，并且使用差异超离心收获小EV。这些小EV每4天鼻内（IN）给予非转基因（NT）或5XFAD（5种家族性阿尔茨海默病突变）小鼠，持续4个月。然后要求小鼠进行各种行为测定，以测量学习和记忆的变化。然后，在脑切片上进行免疫组织化学以测量淀粉样蛋白β（Aβ）和胶质细胞酸性蛋白（GFAP）水平。结果如下：数据显示，接受hMSC-EV治疗的5XFAD小鼠在认知测试中的表现显著优于盐水治疗的5XFAD小鼠，EV治疗的5XFAD小鼠和NT小鼠之间没有显著变化。此外，我们发现EV治疗小鼠海马中的Aβ斑块负荷较低。最后，与盐水相比，在EV治疗的小鼠的脑中发现GFAP和Aβ斑块之间的共定位较少。结论：综上所述，这些数据表明，MSC衍生的EV的IN施用可以减缓AD发病。
Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that affects more than 44 million people worldwide. Despite the high disease burden, there is no effective treatment for people suffering from AD. Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been widely studied due to their therapeutic potential. However, administration of cells has been found to have a multitude of limitations. Recently, extracellular vesicles (EVs) derived from MSCs have been studied as a therapeutic candidate, as they exhibit similar immunoprotective and immunomodulatory abilities as the host human MSCs. Methods: To test the potential therapeutic effects of MSC EVs, human bone-marrow derived MSCs were grown in three-dimensional (3D) cell culture, and small EVs were harvested using differential ultracentrifugation. These small EVs were given to non-transgenic (NT) or 5XFAD (5 familial Alzheimer's disease mutations) mice intranasally (IN) every 4 days for 4 months. The mice were then required to perform a variety of behavioral assays to measure changes in learning and memory. Afterwards, immunohistochemistry was performed on brain slices to measure amyloid beta (Aβ) and glial fibrillary acidic protein (GFAP) levels. Results: The data revealed that 5XFAD mice that received hMSC-EV treatment behaved significantly better in cognitive tests than saline treated 5XFAD mice, with no significant change between EV-treated 5XFAD mice and NT mice. Additionally, we found lower Aβ plaque load in the hippocampus of the EV-treated mice. Finally, less colocalization between GFAP and Aβ plaques was found in the brain of EV-treated mice compared to saline. Conclusions: Taken together, these data suggest that IN administration of MSC-derived EVs can slow down AD pathogenesis.