Department of Thoracic Surgery, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, 646000, Sichuan, China.
Department of Thoracic Surgery/Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Stem Cell Rev Rep. 2022 Mar;18(3):1007-1024. doi: 10.1007/s12015-021-10311-x. Epub 2021 Dec 9.
Hyperoxia-induced lung injury (HILI) tends to develop bronchopulmonary dysplasia. Adipose-derived mesenchymal stem cell (ADMSC)-derived extracellular vesicles (EVs) hold great promise in alleviating lung injury. This study explored the mechanism of ADMSC-EVs in HILI. ADMSC-EVs were isolated and identified. The murine and cell models of HILI were established. HILI mice and cells were pre-treated with ADMSC-EVs. The lung dry/wet ratio, pathological structure, apoptosis, and inflammation of HILI mice were measured. The viability, apoptosis, and oxidative stress of HILI cells were measured. The internalization of EVs in lung and cells was observed by fluorescence labeling. The binding relationships between miR-21-5p and SKP2, and Nr2f2 and C/EBPα were analyzed. The binding of SKP2 and Nr2f2 and the Nr2f2 ubiquitination level were detected. ADMSC-EVs exerted preventive effects on HILI mice, evidenced by reduced lung dry/wet ratio, inflammation, and apoptosis in HILI mice. In vitro, EVs enhanced HILI cell viability and reduced apoptosis, inflammation, and oxidative stress. EVs carried miR-21-5p into lung cells to upregulate miR-21-5p expression and thereby target SKP2. SKP2 bound to Nr2f2 and promoted its ubiquitination degradation. EVs inhibited the binding of Nr2f2 and C/EBPα and further suppressed C/EBPα transcription. Collectively, ADMSC-EVs carrying miR-21-5p alleviated HILI via the SKP2/Nr2f2/C/EBPα axis. Role and mechanism of adipose-derived mesenchymal stem cell-derived extracellular vesicles in hyperoxia-induced lung injury. ADMSC-EVs upregulated miR-21-5p expression in cells by carrying miR-21-5p into lung cells, thereby promoting the binding of miR-21-5p and SKP2 mRNA, inhibiting the expression of SKP2, reducing the ubiquitination level of Nr2f2, increasing the expression of Nr2f2, promoting the binding of Nr2f2 and the C/EBPα promoter, upregulating C/EBPα mRNA level, and eventually alleviating HILI.
高氧诱导性肺损伤（HILI）往往会发展为支气管肺发育不良。脂肪间充质干细胞（ADMSC）衍生的细胞外囊泡（EVs）在缓解肺损伤方面具有很大的应用前景。本研究探讨了 ADMSC-EVs 在 HILI 中的作用机制。分离并鉴定 ADMSC-EVs，建立 HILI 小鼠和细胞模型，对 HILI 小鼠和细胞进行 ADMSC-EVs 预处理，检测 HILI 小鼠的肺干湿比、病理结构、细胞凋亡和炎症反应，检测 HILI 细胞的活力、凋亡和氧化应激。通过荧光标记观察 EVs 在肺和细胞中的内化，分析 miR-21-5p 与 SKP2 及 Nr2f2 与 C/EBPα 的结合关系，检测 SKP2 与 Nr2f2 的结合及 Nr2f2 的泛素化水平。ADMSC-EVs 对 HILI 小鼠具有预防作用，可降低 HILI 小鼠的肺干湿比、炎症和细胞凋亡。在体外，EVs 增强了 HILI 细胞的活力，降低了细胞凋亡、炎症和氧化应激。EVs 将 miR-21-5p 带入肺细胞，上调 miR-21-5p 的表达，从而靶向 SKP2。SKP2 与 Nr2f2 结合，并促进其泛素化降解。EVs 抑制 Nr2f2 与 C/EBPα 的结合，进一步抑制 C/EBPα 的转录。综上所述，携带 miR-21-5p 的 ADMSC-EVs 通过 SKP2/Nr2f2/C/EBPα 轴缓解 HILI。脂肪间充质干细胞衍生的细胞外囊泡在高氧诱导性肺损伤中的作用及机制。ADMSC-EVs 通过将 miR-21-5p 带入肺细胞，上调细胞内 miR-21-5p 的表达，从而促进 miR-21-5p 与 SKP2mRNA 的结合，抑制 SKP2 的表达，降低 Nr2f2 的泛素化水平，增加 Nr2f2 的表达，促进 Nr2f2 与 C/EBPα 启动子的结合，上调 C/EBPαmRNA 水平，最终缓解 HILI。
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