Priming Mesenchymal Stem Cells with Lipopolysaccharide Boosts the Immunomodulatory and Regenerative Activity of Secreted Extracellular Vesicles.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Aina Areny-Balagueró, Marta Camprubí-Rimblas, Elena Campaña-Duel, Anna Solé-Porta, Adrián Ceccato, Anna Roig, John G Laffey, Daniel Closa, Antonio Artigas
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引用次数: 0

Abstract

Background: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as an alternative to live-cell administration for Acute Respiratory Distress Syndrome (ARDS). MSC-EVs can be chiefly influenced by the environment to which the MSCs are exposed. Here, lipopolysaccharide (LPS) priming of MSCs was used as a strategy to boost the natural therapeutic potential of the EVs in acute lung injury (ALI). Methods: The regenerative and immunemodulatory effect of LPS-primed MSC-EVs (LPS-EVs) and non-primed MSC-EVs (C-EVs) were evaluated in vitro on alveolar epithelial cells and macrophage-like THP-1 cells. In vivo, ALI was induced in adult male rats by the intrapulmonary instillation of HCl and LPS. Rats (n = 8 to 22/group) were randomized to receive a single bolus (1 × 108 particles) of LPS-EVs, C-EVs, or saline. Lung injury severity was assessed at 72 h in lung tissue and bronchoalveolar lavage. Results: In vitro, LPS-EVs improved wound regeneration and attenuated the inflammatory response triggered by the P. aeruginosa infection, enhancing the M2 macrophage phenotype. In in vivo studies, LPS-EVs, but not C-EVs, significantly decreased the neutrophilic infiltration and myeloperoxidase (MPO) activity in lung tissue. Alveolar macrophages from LPS-EVs-treated animals exhibited a reduced expression of CXCL-1, a key neutrophil chemoattractant. However, both C-EVs and LPS-EVs reduced alveolar epithelial and endothelial permeability, mitigating lung damage. Conclusions: EVs from LPS-primed MSCs resulted in a better resolution of ALI, achieving a greater balance in neutrophil infiltration and activation, while avoiding the complete disruption of the alveolar barrier. This opens new avenues, paving the way for the clinical implementation of cell-based therapies.

用脂多糖诱导间充质干细胞可增强分泌型细胞外囊泡的免疫调节和再生活性
背景:间充质干细胞(MSCs)衍生的细胞外囊泡(EVs)已被提议作为急性呼吸窘迫综合征(ARDS)活细胞给药的替代方法。间充质干细胞产生的细胞外囊泡主要受间充质干细胞所处环境的影响。在这里,间充质干细胞的脂多糖(LPS)引物被用作一种策略,以提高EVs在急性肺损伤(ALI)中的天然治疗潜力。方法在体外评估了LPS引物间充质干细胞-EVs(LPS-EVs)和非引物间充质干细胞-EVs(C-EVs)对肺泡上皮细胞和巨噬细胞样THP-1细胞的再生和免疫调节作用。在体内,通过向成年雄性大鼠肺内灌注盐酸和LPS诱发ALI。大鼠(n = 8 至 22 只/组)被随机分配接受单次注射(1 × 108 颗粒)LPS-EVs、C-EVs 或生理盐水。72 小时后评估肺组织和支气管肺泡灌洗液的肺损伤严重程度。结果显示在体外,LPS-EVs 可改善伤口再生,减轻铜绿假单胞菌感染引发的炎症反应,增强 M2 巨噬细胞表型。在体内研究中,LPS-EVs(而非 C-EVs)能显著减少肺组织中的中性粒细胞浸润和髓过氧化物酶(MPO)活性。经 LPS-EVs 处理的动物肺泡巨噬细胞的 CXCL-1 表达量减少,而 CXCL-1 是一种关键的中性粒细胞趋化诱导剂。不过,C-EVs 和 LPS-EVs 都能降低肺泡上皮和内皮的通透性,减轻肺损伤。结论LPS刺激的间充质干细胞产生的EV能更好地缓解ALI,在中性粒细胞浸润和活化方面实现更大的平衡,同时避免完全破坏肺泡屏障。这开辟了新的途径,为基于细胞的疗法的临床应用铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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