脂肪干细胞来源的外泌体减轻新生大鼠支气管肺发育不良并调节自噬。

Yuanyuan Sun, Cuie Chen, Yuanyuan Liu, Anqun Sheng, Shi Wang, Xixi Zhang, Dan Wang, Qiu Wang, Chaosheng Lu, Zhenlang Lin
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引用次数: 0

摘要

背景:间充质干细胞衍生的外泌体(MSC-Exos)疗法在与新生儿医学相关的病理学临床前模型中显示出了前景,如支气管肺发育不良(BPD)。脂肪来源的干细胞(ADSCs)已被公认为最有前途的干细胞来源之一。自噬在调节细胞内条件、维持细胞生长发育以及参与BPD的发病机制中发挥着关键作用。目的:研究ADSC-Exos对BPD的潜在治疗作用,并阐明自噬在这一过程中的作用。方法:通过超速离心从培养基中分离出ADSC-Exos,并通过透射电子显微镜(TEM)、纳米颗粒跟踪分析(NTA)和蛋白质印迹(WB)进行表征。新生大鼠暴露于高氧(90%O2)以模拟BPD,在出生后第4天(P4)通过气管内或静脉内给药用ADSC-Exos治疗,并在P7返回室内空气直到P14。在P7和P14采集处理的动物和适当的对照,用于评估肺参数。结果:暴露于高氧的大鼠肺泡明显简化,径向肺泡计数(RAC)降低,平均线性截距(MLI)增加,血管内皮生长因子(VEGF)和CD31表达降低,血管发育受损,TNF-α、IL-1β和IL-6表达增加,IL-10表达降低,刺激炎症。同时,高氧暴露的大鼠通过较低水平的Beclin1、LC3B、LC3BII/I比率和较高水平的p62阻断自噬流量。ADSC-Exos给药保护新生儿肺组织免受高氧诱导的肺泡和血管发育停滞的影响,减少炎症,促进自噬。气管内给药比静脉给药更有效。结论:气管内给予ADSC-Exos可显著改善高氧诱导的BPD的肺泡化和肺血管化阻滞,这在一定程度上与促进自噬有关。
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Adipose Stem Cells Derived Exosomes Alleviate Bronchopulmonary Dysplasia and Regulate Autophagy in Neonatal Rats.

Background: Mesenchymal stem cell-derived exosomes (MSC-Exos) therapies have shown prospects in preclinical models of pathologies relevant to neonatal medicine, such as bronchopulmonary dysplasia (BPD). Adipose-derived stem cells (ADSCs) have been recognized as one of the most promising stem cell sources. Autophagy plays a key role in regulating intracellular conditions, maintaining cell growth and development, and participating in the pathogenesis of BPD.

Objectives: To investigate the potential therapeutic role of ADSC-Exos on BPD and to illustrate the role of autophagy in this process.

Method: ADSC-Exos was isolated from media conditioned of ADSCs by ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting (WB). Newborn rats were exposed to hyperoxia (90% O2) from postnatal day 0 (P0) to P7, and returned to room air until P14 to mimic BPD. ADSC-Exos was treated by intratracheal or intravenous administration on P4. Treated animals and appropriate controls were harvested on P7 and P14 for assessment of pulmonary parameters.

Results: Hyperoxia-exposed rats were presented with pronounced alveolar simplification with decreased radial alveolar count (RAC) and increased mean linear intercept (MLI), impaired vascular development with low vascular endothelial growth factor (VEGF) and CD31 expression, and stimulated inflammation with increased expression of TNF-α, IL-1β, and IL-6, and decreased expression of IL-10. Meanwhile, the rats with hyperoxia exposure blocked autophagic flux with lower levels of Beclin1, LC3B, LC3BII/I ratio and higher levels of p62. ADSC-Exos administration protected the neonatal lung tissues from the hyperoxia-induced arrest of alveolar and vascular development, reduced inflammation, and facilitated autophagy. Intratracheal administration was more efficacious than intravenous administration.

Conclusion: The intratracheal administration of ADSC-Exos significantly improved alveolarization and pulmonary vascularization arrest in hyperoxia-induced BPD, which was associated with facilitating autophagy in part.

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