Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia Role of Neuregulin-1
Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia Role of Neuregulin-1
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DOI：
10.1161/atvbaha.119.313506
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发表时间：
2020-01-01
影响因子：
8.7
通讯作者：
Brizzi, Maria Felice
中科院分区：
文献类型：
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作者：
Figliolini, Federico;Ranghino, Andrea;Brizzi, Maria Felice
目的：严重的后肢缺血是外周动脉疾病的严重后果。手术治疗不能预防骨骼肌损伤或改善患者的长期预后。本研究探讨了脂肪干细胞来源的细胞外囊泡（ASC-EV）在小鼠后肢缺血模型中的保护/再生潜力及其作用机制。方法和结果：我们证明 ASC-EV 通过作用于组织微血管和肌肉细胞，对肌肉损伤发挥保护作用。在 ASC-EV 治疗的动物的缺血肌肉中，参与肌肉再生的基因上调。 MyoD 表达也在卫星细胞中得到证实。随后体内肌肉功能损伤减少。 ASC-EV 在体外缺血/复氧模型中驱动成肌细胞增殖和分化。此外，ASC-EVs 在体外和体内均显示出抗凋亡作用。转录组分析表明，ASC-EV 携带多种促血管生成 mRNA，而蛋白质组分析表明 NRG1（神经调节蛋白 1）富集。体内使用的 NRG1 阻断抗体证明 NRG1 与 ASC-EV 诱导的肌肉保护、血管生长和炎症细胞的募集相关。最后，对 ASC-EV 中常见的 18 种分子（包括 mRNA 和蛋白质）进行生物信息学分析，证实了参与血管生长和肌肉再生/保护的途径的富集。结论：本研究表明，ASC-EV 表现出与其 NRG1/mRNA 货物相关的促血管生成和骨骼肌保护特性。因此，我们认为 ASC-EV 是治疗性血管生成和肌肉保护的有用工具。
Objectives: Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia. Approach and Results: We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection. Conclusions: This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.