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-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.

Systematic review of extracellular vesicle‐based treatments for lung injury: are EVs a potential therapy for COVID‐19?

“…Of the 4,925 titles and abstracts screened, 233 articles were reviewed, 90 were assessed for eligibility and 39 were included in the final analysis (Figure 2) [31–69]. The selected studies were published between 2014 and 2020 and included in vitro, ex vivo , and in vivo studies (Table 2).…”

“…In studies modelling pneumonia, EVs induced adaptive immunity and reduced bacterial load [67]. Studies that tested EVs on models of pulmonary fibrosis reported that EV treatment reduced collagen deposition and density, halted fibrosis progression by inhibiting myofibroblast differentiation, and improved the Ashcroft score, a standard scoring system for pulmonary fibrosis [32,43,50,65].…”

MicroRNAs from Liquid Biopsy Derived Extracellular Vesicles: Recent Advances in Detection and Characterization Methods

“…Current studies focus on the extracellular vesicles mainly isolated from human blood, or, respectively, serum or plasma [ 71 , 72 , 73 , 74 ]. However, extracellular vesicles can be isolated from a broad variety of human body fluids such as urine [ 75 , 76 ], saliva [ 77 , 78 ], bronchoalveolar liquid [ 79 ], pleural lavage [ 80 ], and cerebrospinal fluid [ 81 ] and even more uncommon ones like tears [ 82 ], semen [ 83 ], menstrual blood [ 84 ], peritoneal lavage [ 85 , 86 ], bile [ 87 ], and pancreatic juice [ 88 ]. An overview of non-coding RNAs that were analyzed in extracellular vesicles isolated from different liquid biopsies of different kinds is presented in Table 1 .…”

Therapeutic Potential of Exosomes in Pulmonary Fibrosis

“…BMSCs promote an immunoregulatory, anti-inflammatory monocyte phenotype to prevent PF (Mansouri et al, 2019). Exosomal let-7 from menstrual blood-derived endometrial stem cells alleviates lung fibrosis and alveolar epithelial cell damage in mice by regulating reactive oxygen species levels, mitochondrial DNA damage and NLRP3 inflammasome activation (Sun et al, 2019). Lung fibroblast-derived EVs from IPF patients were shown to increase mitochondrial reactive oxygen species levels and associated mitochondrial damage in lung epithelial cells, and these EVs were sown to contain elevated levels of miR-23b-3p and miR-494-3p (Kadota et al, 2020).…”