Rationale: Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos). Objective: To assess efficacy of MSC-exo treatment in a pre-clinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action. Methods: Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX, 75% O2), treated with exosomes on postnatal day 4 (PN4) and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, 14 or 42 for assessment of pulmonary parameters. Measurements and Main Results: HYRX-exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements following MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC-exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory M1 state and augmenting an anti-inflammatory M2-like state, both in vitro and in vivo. Conclusion: MSC-exo treatment blunts hyperoxia-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX-induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC exosome mechanism-of-action is associated with modulation of lung macrophage phenotype.

中文翻译：

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间充质基质细胞外泌体可改善实验性支气管肺发育不良并通过巨噬细胞免疫调节恢复肺功能。

原理：间充质干/基质细胞（MSC）治疗在与新生医学相关的病理学临床前模型中显示出了希望，例如支气管肺发育不良（BPD）。我们已经报道了MSC的治疗能力包含在它们的分泌组中，并且证明了治疗载体是由MSC产生的外来体（MSC-exos）。目的：评估临床前BPD模型中MSC-exo治疗的疗效，并探讨MSC-exo治疗作用的潜在机制。方法：从人MSC培养条件下的培养基中分离外泌体。新生小鼠暴露于高氧血症（HYRX，75％O2），在出生后第4天（PN4）用外泌体处理，并在PN7上回到室内。在PN7、14或42上收获经治疗的动物和适当的对照以评估肺参数。测量和主要结果：暴露于HYRX的小鼠表现出明显的肺泡简化，纤维化和肺血管重塑，通过MSC-exo治疗可有效改善。肺功能测试和肺动脉高压评估显示，MSC-exo治疗后功能得到改善。肺mRNA测序证明，MSC-exo处理对与HYRX诱导的炎症和免疫反应相关的基因表达具有多效性作用。MSC-exos在体外和体内均可调节巨噬细胞表型支点，抑制促炎性M1状态并增强抗炎性M2样状态。结论：MSC-exo治疗可钝化高氧相关的炎症并改变高氧肺转录组。这样可以减轻HYRX诱导的BPD，改善肺功能，减少纤维化和肺血管重构，并改善肺动脉高压。MSC外泌体的作用机制与肺巨噬细胞表型的调节有关。