Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization.
Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization.
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DOI：
10.1002/sctm.16-0363
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发表时间：
2017-03
影响因子：
6
通讯作者：
Tasso R
中科院分区：
文献类型：
--
作者：
Lo Sicco C;Reverberi D;Balbi C;Ulivi V;Principi E;Pascucci L;Becherini P;Bosco MC;Varesio L;Franzin C;Pozzobon M;Cancedda R;Tasso R
间充质干细胞（MSC）是有效的治疗剂，主要通过其旁分泌活性增强损伤组织的修复。越来越多的证据表明，除了可溶性分子的分泌，细胞外囊泡（EVs）的释放代表了MSC采用的另一种机制。由于巨噬细胞是解决炎症的重要贡献者，这已经成为一个精心策划的过程，本研究的目的是对人脂肪来源的MSC释放的EV进行详细表征，以研究它们作为MSC抗炎作用的调节剂诱导巨噬细胞极化的参与。EV分离方法基于暴露于常氧或低氧条件的MSC条件培养基的重复超浓缩（EVNormo和EVHypo）。两种类型的EV都被应答的骨髓源性巨噬细胞有效地内化，引发它们从M1表型转变为M2表型。在体内，心脏毒素诱导的骨骼肌损伤后，EVNormo和EVHypo与初始炎症反应期间招募的巨噬细胞相互作用。在受损和EV治疗的肌肉中，IL 6和先天性和经典激活的早期标志物Nos 2的下调与替代激活的晚期标志物Arg1和Ym 1的显著上调以及浸润CD206pos细胞百分比的增加同时发生。这些作用伴随着生肌标志物Pax7、MyoD和eMyhc的加速表达，在EVHypo给药后甚至更大。总的来说，这些数据表明MSC-EV具有有效的抗炎特性，使其成为比MSC更方便和安全的潜在治疗剂。干细胞转化医学2017干细胞转化医学2017; 6：1018 - 1028
Mesenchymal Stem Cells (MSCs) are effective therapeutic agents enhancing the repair of injured tissues mostly through their paracrine activity. Increasing evidences show that besides the secretion of soluble molecules, the release of extracellular vesicles (EVs) represents an alternative mechanism adopted by MSCs. Since macrophages are essential contributors toward the resolution of inflammation, which has emerged as a finely orchestrated process, the aim of the present study was to carry out a detailed characterization of EVs released by human adipose derived‐MSCs to investigate their involvement as modulators of MSC anti‐inflammatory effects inducing macrophage polarization. The EV‐isolation method was based on repeated ultracentrifugations of the medium conditioned by MSC exposed to normoxic or hypoxic conditions (EVNormo and EVHypo). Both types of EVs were efficiently internalized by responding bone marrow‐derived macrophages, eliciting their switch from a M1 to a M2 phenotype. In vivo, following cardiotoxin‐induced skeletal muscle damage, EVNormo and EVHypo interacted with macrophages recruited during the initial inflammatory response. In injured and EV‐treated muscles, a downregulation of IL6 and the early marker of innate and classical activation Nos2 were concurrent to a significant upregulation of Arg1 and Ym1, late markers of alternative activation, as well as an increased percentage of infiltrating CD206pos cells. These effects, accompanied by an accelerated expression of the myogenic markers Pax7, MyoD, and eMyhc, were even greater following EVHypo administration. Collectively, these data indicate that MSC‐EVs possess effective anti‐inflammatory properties, making them potential therapeutic agents more handy and safe than MSCs. stem cells translational medicine 2017 Stem Cells Translational Medicine 2017;6:1018–1028