Extracellular Vesicles Mediate Mesenchymal Stromal Cell-Dependent Regulation of B Cell PI3K-AKT Signaling Pathway and Actin Cytoskeleton
Extracellular Vesicles Mediate Mesenchymal Stromal Cell-Dependent Regulation of B Cell PI3K-AKT Signaling Pathway and Actin Cytoskeleton
复制标题
DOI：
10.3389/fimmu.2019.00446
复制
发表时间：
2019-03-12
影响因子：
7.3
通讯作者：
Krampera, Mauro
中科院分区：
文献类型：
--
作者：
Adamo, Annalisa;Brandi, Jessica;Krampera, Mauro
间充质基质细胞（MSC）是中胚层来源的成体多能细胞，代表所有基质组织的祖细胞。MSC具有显著和广泛的免疫调节功能，一旦MSC被炎症微环境引发，其影响适应性和先天性免疫应答。最近，细胞外囊泡（EV）在介导MSC的治疗效果中的作用已被认识到。然而，负责MSC衍生的EV（MSC-EV）的免疫调节特性的分子机制仍然很差的特点。因此，我们通过高通量方法对MSC-EV内容物进行了分子表征。我们分析了正常和炎症条件下细胞和囊泡隔室中的miRNA和蛋白质表达谱。我们发现了几种参与免疫过程的蛋白质和miRNA，如MOES，LG 3BP，PTX 3和S10 A6蛋白，miR-155- 5 p和miR-497- 5 p。还进行了不同的计算机模拟方法，以关联miRNA和蛋白质表达谱，然后评估参与MSC-EV介导的免疫调节特性的推定分子或途径。PI 3 K-AKT信号通路和肌动蛋白细胞骨架的调节被鉴定并在体外功能上被验证为MSC-EV介导的MSC/B细胞通讯的关键介质。总之，我们确定了负责MSC-EV介导的免疫调节特性的不同分子和途径，从而确定了新的治疗靶点，作为基于细胞或EV的治疗方法的更安全和更有用的替代方案。
Mesenchymal stromal cells (MSCs) are adult, multipotent cells of mesodermal origin representing the progenitors of all stromal tissues. MSCs possess significant and broad immunomodulatory functions affecting both adaptive and innate immune responses once MSCs are primed by the inflammatory microenvironment. Recently, the role of extracellular vesicles (EVs) in mediating the therapeutic effects of MSCs has been recognized. Nevertheless, the molecular mechanisms responsible for the immunomodulatory properties of MSC-derived EVs (MSC-EVs) are still poorly characterized. Therefore, we carried out a molecular characterization of MSC-EV content by high-throughput approaches. We analyzed miRNA and protein expression profile in cellular and vesicular compartments both in normal and inflammatory conditions. We found several proteins and miRNAs involved in immunological processes, such as MOES, LG3BP, PTX3, and S10A6 proteins, miR-155-5p, and miR-497-5p. Different in silico approaches were also performed to correlate miRNA and protein expression profile and then to evaluate the putative molecules or pathways involved in immunoregulatory properties mediated by MSC-EVs. PI3K-AKT signaling pathway and the regulation of actin cytoskeleton were identified and functionally validated in vitro as key mediators of MSC/B cell communication mediated by MSC-EVs. In conclusion, we identified different molecules and pathways responsible for immunoregulatory properties mediated by MSC-EVs, thus identifying novel therapeutic targets as safer and more useful alternatives to cell or EV-based therapeutic approaches.