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

الملخص EN

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-β1-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.