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Mesenchymal stem cells-derived exosomes carrying microRNA-30b confer protection against pulmonary fibrosis by downregulating Runx1 via Spred2

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary fibrosis disease that is fatal. Mesenchymal stem cells (MSCs)-secreted exosomes (exos) have been linked to improving PF. Moreover, exosomal microRNAs (miRs) can control the growth of numerous diseases, including lung disorders. Our bioinformatics analysis showed that miR-30b was downregulated in tissue samples from surgical remnants of biopsies or lungs explanted from patients with IPF who underwent pulmonary transplantation. This suggests that miR-30b plays an important role in both the pathogenesis and treatment of IPF. Herein, this research was designed to ascertain the mechanism of MSCs-exos-packaged miR-30b in alleviating PF. The serum was harvested from idiopathic PF (IPF) patients with interstitial pneumonia caused by dermatomyositis and the MLE12 lung epithelial cell fibrosis model was built with TGF-β1 (10 ng/mL), followed by miR-30b expression determination. TGF-β1-stimulated MLE12 cells were co-incubated with exos from MSCs with or without Spred2 or Runx1 overexpression, followed by measurement of cell viability and apoptosis. After establishing the IPF mouse model with bleomycin and injecting exos and/or silencing and overexpressing adenovirus vectors, fibrosis evaluation was conducted. In mice and cells, the expression of TGF-β1, TNF-α, and IL-1β was tested via ELISA, and the levels of E-cad, ZO-1, α-SMA, and collagen type I via western blot analysis. The promoters of miR-30b, Runx1, and Spred2 were investigated. miR-30b was downregulated in the serum of IPF patients and TGF-β1-stimulated MLE12 cells. Mechanistically, miR-30b inhibited Spred2 transcription by negatively targeting Runx1. MSCs-exos or MSCs-exo-miR-30b decreased the apoptosis, inflammation, and fibrosis while increasing their viability in TGF-β1-stimulated MLE12 cells, which was annulled by overexpressing Runx1 or Spred2. Exo-miR-30b decreased Runx1 expression to downregulate Spred2, reducing fibrosis and inflammation in IPF mice. Our results indicated that MSCs-exos-encapsulated miR-30b had a potential function to inhibit PF and part of its function may be achieved by targeting RUNX1 to reduce the Spred2 transcription level. Moreover, this work offered evidence and therapeutic targets for therapeutic strategies for managing clinical PF in patients.

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Author notes

  1. Liang Zhu and Yun Xu are co-first authors.

Authors and Affiliations

  1. Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No.88, Jiefang Rd, Shangcheng District, Hangzhou, 310009, Zhejiang, People’s Republic of China

    Liang Zhu & Huaxiang Wu

  2. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, People’s Republic of China

    Yun Xu

  3. Department of Nephrology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, People’s Republic of China

    Jianqing Wang

  4. School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People’s Republic of China

    Yi Zhang & Jiawang Zhou

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  1. Liang Zhu
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Contributions

ZL and XY contributed equally to this research. ZL and XY conceived the ideas. ZL, XY, WJQ, ZY, and WXH designed the experiments. ZL, XY, WJQ, ZY, and ZJW performed the experiments. ZL, XY, and WXH analyzed the data. ZL and XY provided critical materials. ZY, XY, WJQ, and ZY wrote the manuscript. WHX supervised the study. All the authors have read and approved the final version for publication.

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Correspondence to Huaxiang Wu.

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Ethical approval

This study was approved by the Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine and fully complied with the declaration of Helsinki. All participants were signed informed consent forms.

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Communicated by Martine Collart.

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Zhu, L., Xu, Y., Wang, J. et al. Mesenchymal stem cells-derived exosomes carrying microRNA-30b confer protection against pulmonary fibrosis by downregulating Runx1 via Spred2. Mol Genet Genomics 299, 33 (2024). https://doi.org/10.1007/s00438-024-02116-7

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