Adipose-Derived Mesenchymal Stem Cells Ameliorate Chronic Experimental Autoimmune Encephalomyelitis
Adipose-Derived Mesenchymal Stem Cells Ameliorate Chronic Experimental Autoimmune Encephalomyelitis
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DOI：
10.1002/stem.194
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发表时间：
2009-10-01
期刊：
影响因子：
5.2
通讯作者：
Bonetti, Bruno
中科院分区：
文献类型：
--
作者：
Constantin, Gabriela;Marconi, Silvia;Bonetti, Bruno
间充质干细胞（MSCs）是治疗神经自身免疫性疾病的一种有前景的治疗方法；先前的研究表明，用骨髓来源的间充质干细胞治疗可诱导免疫调节，并降低实验性自身免疫性脑脊髓炎（EAE，多发性硬化的一种动物模型）的疾病严重程度。在此我们表明，在疾病发作前静脉注射脂肪来源的间充质干细胞（ASCs）可通过免疫调节显著降低EAE的严重程度，并减少脊髓炎症和脱髓鞘。ASCs优先归巢到淋巴器官，但也迁移到中枢神经系统（CNS）内部。最重要的是，在慢性已确诊的EAE中施用ASCs可显著改善疾病进程，减少脱髓鞘和轴突丢失，并诱导T细胞中Th2型细胞因子的转变。有趣的是，在活体显微镜实验中，一部分相关的ASCs表达活化的α4整合素并黏附到发炎的脑小静脉。生物发光成像显示α(4)整合素控制ASCs在发炎的中枢神经系统中的积聚。重要的是，我们发现ASC培养物产生碱性成纤维细胞生长因子、脑源性生长因子和血小板源性生长因子 - AB。此外，ASCs在脱髓鞘区域内的浸润伴随着内源性少突胶质细胞祖细胞数量的增加。总之，我们表明ASCs通过一种双模式机制具有明确的治疗潜力，既在疾病早期抑制自身免疫反应，又在已确诊疾病的动物中通过内源性祖细胞诱导局部神经再生。总体而言，我们的数据表明ASCs是中枢神经系统慢性炎症疾病中基于干细胞治疗的一种有价值的工具。《干细胞》2009年；27卷：2624 - 2635页
Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for neurological autoimmune diseases; previous studies have shown that treatment with bone marrow-derived MSCs induces immune modulation and reduces disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Here we show that intravenous administration of adipose-derived MSCs (ASCs) before disease onset significantly reduces the severity of EAE by immune modulation and decreases spinal cord inflammation and demyelination. ASCs preferentially home into lymphoid organs but also migrates inside the central nervous system (CNS). Most importantly, administration of ASCs in chronic established EAE significantly ameliorates the disease course and reduces both demyelination and axonal loss, and induces a Th2-type cytokine shift in T cells. Interestingly, a relevant subset of ASCs expresses activated alpha 4 integrins and adheres to inflamed brain venules in intravital microscopy experiments. Bioluminescence imaging shows that alpha(4) integrins control ASC accumulation in inflamed CNS. Importantly, we found that ASC cultures produce basic fibroblast growth factor, brain-derived growth factor, and platelet-derived growth factor-AB. Moreover, ASC infiltration within demyelinated areas is accompanied by increased number of endogenous oligodendrocyte progenitors. In conclusion, we show that ASCs have clear therapeutic potential by a bimodal mechanism, by suppressing the autoimmune response in early phases of disease as well as by inducing local neuroregeneration by endogenous progenitors in animals with established disease. Overall, our data suggest that ASCs represent a valuable tool for stem cell-based therapy in chronic in. ammatory diseases of the CNS. STEM CELLS 2009;27:2624-2635