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Exosomal miRNA Let-7 from Menstrual Blood-Derived Endometrial Stem Cells Alleviates Pulmonary Fibrosis through Regulating Mitochondrial DNA Damage.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease with high morbidity and high mortality. Menstrual blood-derived stem cells (MenSCs) have proven to be an attractive tool for the treatment of acute lung injury and fibrosis-related diseases through immunosuppression and antifibrosis. However, whether MenSC-derived exosomes have the similar function on pulmonary fibrosis remains unclear. In the present study, exosomes secreted from MenSCs (MenSCs-Exo) were verified by transmission electron microscope (TEM), nanoparticle tracking analyzer (NTA), and western blotting. And MenSC-Exo addition significantly improved BLM-induced lung fibrosis and alveolar epithelial cell damage in mice, mainly reflected in BLM-mediated enhancement of the fibrosis score, blue collagen deposition, dry/wet gravity ratio, hydroxyproline and malondialdehyde levels, and downregulation of glutathione peroxidase, which were all robustly reversed by MenSC-Exo management. Additionally, BLM- and TGF-?1-evoked cellular reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and cell apoptosis were rescued by MenSCs-Exo in vivo and in vitro. Further study indicated that the MenSCs-Exo could transport miRNA Let-7 into recipient alveolar epithelial cells. Let-7 inhibitor administration significantly blocked the exosome-mediated improvement role on lung fibrosis in mice. Mechanistically, Let-7 was able to regulate the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) through binding to its 3'-UTR region. Forced expression of LOX1 promoted the expression of apoptosis-related protein and mtDNA damage markers via regulating NLRP3 which was also confirmed in BLM model mice under the combination therapy of the exosome and Let-7 inhibitor. Collectively, this study demonstrates that exosomal Let-7 from MenSCs remits pulmonary fibrosis through regulating ROS, mtDNA damage, and NLRP3 inflammasome activation. This provides a new approach of exocytosis on the treatment of fibrotic lung disease.

SUBMITTER: Sun L

PROVIDER: S-EPMC6948326 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exosomal miRNA Let-7 from Menstrual Blood-Derived Endometrial Stem Cells Alleviates Pulmonary Fibrosis through Regulating Mitochondrial DNA Damage.

Sun Lifang L Zhu Min M Feng Wei W Lin Yiping Y Yin Jia J Jin Juan J Wang Yunguang Y

Oxidative medicine and cellular longevity 20191216

Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease with high morbidity and high mortality. Menstrual blood-derived stem cells (MenSCs) have proven to be an attractive tool for the treatment of acute lung injury and fibrosis-related diseases through immunosuppression and antifibrosis. However, whether MenSC-derived exosomes have the similar function on pulmonary fibrosis remains unclear. In the present study, exosomes secreted from MenSCs (MenSCs ...[more]

PMID: 31949877

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Project description:Background and aim: Pro-inflammatory macrophages aggravated progress of pulmonary fibrosis (PF) both in patients and animal models. Fuzheng Huayu (FZHY) formula, a Chinese herbal product, is effective in treating pulmonary fibrosis in our previous study. But its action mechanism against PF relating to macrophage activation was unclear. This study was designed to evaluate the anti-fibrotic and anti-inflammatory roles of FZHY in pulmonary fibrosis and to elucidate the potential mechanisms. Methods: Network pharmacology was employed to identify the interrelationships among compounds of FZHY, potential targets and putative pathways on anti-pulmonary fibrosis. According to the data of bioinformatics analysis, the key pharmacological target for FZHY against PF was screened. The network pharmacological prediction was validated by a series of experimental assays, including CCK8, western blot and immunofluorescence staining. Then molecular mechanism of FZHY on relating to the predictive target were studied in bleomycin induced pulmonary fibrosis in mice with methylprednisolone as a positive control, and in lipopolysaccharide (LPS) stimulated cultured macrophages in culture, respectively. Results: The network pharmacology analysis reveal that a total of 12 FZHY-PF crossover proteins were filtered into a protein-protein interaction network complex and designated as the potential targets of FZHY against pulmonary fibrosis, while TNF-α signal pathway ranked at the top. FZHY and methylprednisolone could attenuate the lung fibrosis and decrease pulmonary TNF-α expression in bleomycin induced fibrotic mice, without difference between two treatments. While TNF-α was mainly originated from macrophages identified by double fluorescent staining of TNF-α and F4/80. LPS stimulated cultured macrophage polarization and activation demonstrated by the enhance contents of TNF-α and iNOS but decreased level of Arg-1. FZHY could alleviate the LPS stimulated macrophage polarization and activation demonstrated by decreasing TNF-α and iNOS and increasing Arg-1. In particular, FZHY could significantly reduce the production of p65 and the nuclear translocation of phosphorylated p65. Conclusion: Fuzheng Huayu formula has a good effect against pulmonary fibrosis induced by bleomycin in mice, whose action mechanism was associated with down-regulation of NF-κB/TNF-α signaling pathway in pro-inflammatory macrophages. These findings provided an important strategy for developing new agents against lung fibrosis and accelerated FZHY product application on patients with lung fibrosis.

Dataset Information

Exosomal miRNA Let-7 from Menstrual Blood-Derived Endometrial Stem Cells Alleviates Pulmonary Fibrosis through Regulating Mitochondrial DNA Damage.

Publications

Exosomal miRNA Let-7 from Menstrual Blood-Derived Endometrial Stem Cells Alleviates Pulmonary Fibrosis through Regulating Mitochondrial DNA Damage.

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