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Extracellular vesicles derived from DFO-preconditioned canine AT-MSCs reprogram macrophages into M2 phase.
PLOS ONE ( IF 3.7 ) Pub Date : 2021-07-26 , DOI: 10.1371/journal.pone.0254657
Su-Min Park 1 , Ju-Hyun An 1 , Jeong-Hwa Lee 1 , Kyung-Bo Kim 1 , Hyung-Kyu Chae 1 , Ye-In Oh 1 , Woo-Jin Song 2 , Hwa-Young Youn 1
Affiliation  

BACKGROUND Mesenchymal stem/stromal cells (MSCs) are effective therapeutic agents that ameliorate inflammation through paracrine effect; in this regard, extracellular vesicles (EVs) have been frequently studied. To improve the secretion of anti-inflammatory factors from MSCs, preconditioning with hypoxia or hypoxia-mimetic agents has been attempted and the molecular changes in preconditioned MSC-derived EVs explored. In this study, we aimed to investigate the increase of hypoxia-inducible factor 1-alpha (HIF-1α)/cyclooxygenase-2 (COX-2) in deferoxamine (DFO)-preconditioned canine MSC (MSCDFO) and whether these molecular changes were reflected on EVs. Furthermore, we focused on MSCDFO derived EVs (EVDFO) could affect macrophage polarization via the transfer function of EVs. RESULTS In MSCDFO, accumulation of HIF-1α were increased and production of COX-2 were activated. Also, Inside of EVDFO were enriched with COX-2 protein. To evaluate the transferring effect of EVs to macrophage, the canine macrophage cell line, DH82, was treated with EVs after lipopolysaccharide (LPS) stimulation. Polarization changes of DH82 were evaluated with quantitative real-time PCR and immunofluorescence analyses. When LPS-induced DH82 was treated with EVDFO, phosphorylation of signal transducer and transcription3 (p-STAT3), which is one of key factor of inducing M2 phase, expression was increased in DH82. Furthermore, treated with EVDFO in LPS-induced DH82, the expression of M1 markers were reduced, otherwise, M2 surface markers were enhanced. Comparing with EVDFO and EVnon. CONCLUSION DFO preconditioning in MSCs activated the HIF-1α/COX-2 signaling pathway; Transferring COX-2 through EVDFO could effectively reprogram macrophage into M2 phase by promoting the phosphorylation of STAT3.

中文翻译:

源自 DFO 预处理的犬 AT-MSC 的细胞外囊泡将巨噬细胞重新编程为 M2 期。

背景 间充质干/基质细胞 (MSC) 是通过旁分泌作用改善炎症的有效治疗剂;在这方面,经常研究细胞外囊泡(EV)。为了改善 MSC 的抗炎因子分泌,已经尝试用缺氧或缺氧模拟剂进行预处理,并探索了预处理 MSC 衍生的 EV 的分子变化。在本研究中,我们旨在研究去铁胺 (DFO) 预处理的犬 MSC (MSCDFO) 中缺氧诱导因子 1-α (HIF-1α)/环氧合酶-2 (COX-2) 的增加以及这些分子变化是否是反映在电动汽车上。此外,我们专注于 MSCDFO 衍生的 EV(EVDFO)可以通过 EV 的传递函数影响巨噬细胞极化。结果在 MSCDFO 中,HIF-1α 的积累增加,COX-2 的产生被激活。此外,EVDFO 内部富含 COX-2 蛋白。为了评估 EVs 对巨噬细胞的转移作用,犬巨噬细胞系 DH82 在脂多糖 (LPS) 刺激后用 EVs 处理。DH82 的极化变化通过实时定量 PCR 和免疫荧光分析进行评估。当LPS诱导的DH82用EVDFO处理时,信号转导和转录3(p-STAT3)的磷酸化是诱导M2期的关键因素之一,DH82的表达增加。此外,在 LPS 诱导的 DH82 中用 EVDFO 处理,M1 标记的表达降低,否则,M2 表面标记增强。与 EVDFO 和 EVnon 的比较。结论 MSCs 中 DFO 预处理激活了 HIF-1α/COX-2 信号通路;
更新日期:2021-07-26
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