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Mechanism of Adipose-Derived Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying miR-21-5p in Hyperoxia-Induced Lung Injury

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Abstract

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.

Graphical Abstract

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.

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Data Availability

The data that support this study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Thoracic Surgery, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, 646000, Sichuan, China

    Yunfei Wu

  2. Department of Thoracic Surgery/Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Zhihui Zhang & Xu Wu

  3. Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China

    Jun Li

  4. Department of Cardiothoracic Surgery, Ningbo Yinzhou No.2 Hospital, Ningbo, 315010, Zhejiang, China

    Hai Zhong

  5. Department of Critical Care Medicine, General Hospital of the Chinese People’s Liberation Army, Beijing, 100853, China

    Rui Yuan

  6. Biochemistry Department of Graduate School, General Hospital of the Chinese People’s Liberation Army, Beijing, 100853, China

    Zihui Deng

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  1. Yunfei Wu
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  2. Zhihui Zhang
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Contributions

YW and ZZ made substantial contributions to the conception of the present study. JL, XW and HZ performed the experiments and wrote the manuscript; RY and ZD contributed to the design of the present study and interpreted the data. All authors read and approved the final version of the manuscript for publication.

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Correspondence to Yunfei Wu.

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This study was performed following the approval of the Ethical Committee of the Affiliated Hospital of Southwest Medical University. All animal experiments were implemented based on the Guide for the Care and Use of Laboratory Animals [55].

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Wu, Y., Zhang, Z., Li, J. et al. Mechanism of Adipose-Derived Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying miR-21-5p in Hyperoxia-Induced Lung Injury. Stem Cell Rev and Rep 18, 1007–1024 (2022). https://doi.org/10.1007/s12015-021-10311-x

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