Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University. No. 161, West 5(th) Road, Xincheng District, Xi'an 710003, China.
Mini-invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University. No. 161, West 5(th) Road, Xincheng District, Xi'an 710003, China; Shaanxi Lon-EV Biotechnology Limited Company, No.9 Jiazi, Renyi village, Beilin District, Xi'an 710054, China.
J Control Release. 2022 May;345:214-230. doi: 10.1016/j.jconrel.2022.03.025. Epub 2022 Mar 18.
Mesenchymal stem cell-derived small extracellular vesicles (MSC-EVs) are promising nanotherapeutic agent for pneumonia (bacterial origin, COVID-19), but the optimal administration route and potential mechanisms of action remain poorly understood. This study compared the administration of MSC-EVs via inhalation and tail vein injection for the treatment of acute lung injury (ALI) and determined the host-derived mechanisms that may contribute to the therapeutic effects of MSC-EVs in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (macrophage cell line) and animal models. Luminex liquid chip and hematoxylin and eosin (HE) staining revealed that, compared with the vehicle control, inhaled MSC-EVs outperformed those injected via the tail vein, by reducing the expression of pro-inflammatory cytokines, increasing the expression of anti-inflammatory cytokine, and decreasing pathological scores in ALI. MSC-EV administration promoted the polarization of macrophages towards a M2 phenotype in vitro and in vivo (via inhalation). RNA sequencing revealed that immune and redox mediators, including TLR4, Arg1, and HO-1, were associated with the activity MSC-EVs against ALI mice. Western blotting and immunofluorescence revealed that correlative inflammatory and oxidative mediators were involved in the therapeutic effects of MSC-EVs in LPS-stimulated cells and mice. Moreover, variable expression of Nrf2 was observed following treatment with MSC-EVs in cell and animal models, and knockdown of Nrf2 attenuated the anti-inflammatory and antioxidant activities of MSC-EVs in LPS-stimulated macrophages. Together, these data suggest that inhalation of MSC-EVs as a noninvasive strategy for attenuation of ALI, and the adaptive regulation of Nrf2 may contribute to their anti-inflammatory and anti-oxidant activity in mice.
间充质干细胞衍生的小细胞外囊泡 (MSC-EVs) 是一种有前途的纳米治疗剂，可用于治疗肺炎（细菌性、COVID-19 引起），但最佳给药途径和潜在作用机制仍知之甚少。本研究比较了通过吸入和尾静脉注射 MSC-EVs 治疗急性肺损伤 (ALI) 的效果，并确定了宿主来源的机制，这些机制可能有助于 MSC-EVs 在脂多糖 (LPS) 刺激的 RAW 264.7 细胞（巨噬细胞系）和动物模型中的治疗效果。Luminex 液体芯片和苏木精和伊红 (HE) 染色显示，与载体对照组相比，吸入 MSC-EVs 通过降低促炎细胞因子的表达、增加抗炎细胞因子的表达和降低 ALI 的病理评分，优于通过尾静脉注射的 MSC-EVs。MSC-EV 给药促进了巨噬细胞在体外和体内向 M2 表型的极化（通过吸入）。RNA 测序显示，免疫和氧化还原调节剂，包括 TLR4、Arg1 和 HO-1，与 MSC-EVs 对 ALI 小鼠的活性有关。Western blot 和免疫荧光显示，相关的炎症和氧化介质参与了 MSC-EVs 在 LPS 刺激的细胞和小鼠中的治疗作用。此外，在细胞和动物模型中用 MSC-EVs 治疗后观察到 Nrf2 的可变表达，并且敲低 Nrf2 减弱了 MSC-EVs 在 LPS 刺激的巨噬细胞中的抗炎和抗氧化活性。总之，这些数据表明，吸入 MSC-EVs 作为一种非侵入性策略来减轻 ALI，以及 Nrf2 的适应性调节可能有助于其在小鼠中的抗炎和抗氧化活性。
