Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease in premature newborns, with high morbidity and mortality rates. Mesenchymal stem cell (MSC) transplantation has developed into a promising approach to alleviate BPD. Small extracellular vesicles, which are an important therapeutic component of MSCs, have been reported to be effective in a mouse model of BPD. However, the affected cell types and detailed underlying mechanisms are unclear. In this study, we found that human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) were successfully absorbed by lung tissue after intratracheal administration, and remained in the lungs for at least 72 h. The results showed that hucMSC-sEVs restored alveolar structure and lung function, and ameliorated pulmonary hypertension in a rat model of BPD. The number of Ki-67-positive lung cells were improved, while the number of TUNEL-positive lung cells were reduced in our hucMSC-sEV-treated BPD model. Additionally, SP-C staining (a marker of type II alveolar epithelial cells, TIIAECs) and CD31 staining (a marker of pulmonary vascular endothelial cells, PVECs) were both increased in a hyperoxia-induced BPD model treated with hucMSC-sEVs. In vitro, under hyperoxic conditions, the tube-like structure formation was improved in human umbilical vein endothelial cells, and the proliferation was increased and the apoptosis was attenuated in MLE-12 cells treated with hucMSC-sEVs. Furthermore, we observed downregulated expression of PTEN and cleaved-caspase3, and upregulated expression of p-Akt and vascular endothelial growth factor-A in our hucMSC-sEV-treated BPD model. In conclusion, hucMSC-sEVs improved alveolarization and angiogenesis in a rat BPD model by protecting TIIAECs and PVECs, which were associated with the PTEN/Akt signaling pathway.

中文翻译：

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人脐带间充质干细胞衍生的小细胞外囊泡通过影响细胞存活和血管生成减轻支气管肺发育不良大鼠模型的肺损伤

支气管肺发育不良（BPD）是一种严重的早产儿慢性肺部疾病，发病率和死亡率都很高。间充质干细胞 (MSC) 移植已发展成为缓解 BPD 的一种有前途的方法。据报道，作为 MSC 重要治疗成分的细胞外小囊泡在 BPD 小鼠模型中是有效的。然而，受影响的细胞类型和详细的潜在机制尚不清楚。在这项研究中，我们发现人脐带间充质干细胞衍生的小细胞外囊泡（hucMSC-sEVs）在气管内给药后被肺组织成功吸收，并在肺部保留至少 72 小时。结果表明，hucMSC-sEVs 恢复了 BPD 大鼠模型的肺泡结构和肺功能，并改善了肺动脉高压。在我们的 HucMSC-sEV 处理的 BPD 模型中，Ki-67 阳性肺细胞的数量得到改善，而 TUNEL 阳性肺细胞的数量减少。此外，SP-C 染色（II 型肺泡上皮细胞的标志物，TIIAECs）和 CD31 染色（肺血管内皮细胞的标志物，PVECs）在用 HucMSC-sEVs 治疗的高氧诱导的 BPD 模型中均增加。在体外，在高氧条件下，人脐静脉内皮细胞的管状结构形成得到改善，用 HucMSC-sEVs 处理的 MLE-12 细胞增殖增加，细胞凋亡减弱。此外，我们在我们的 HucMSC-sEV 处理的 BPD 模型中观察到 PTEN 和 cleaved-caspase3 的表达下调，以及 p-Akt 和血管内皮生长因子-A 的表达上调。综上所述，