Adipose-Derived Mesenchymal Stem Cell-Derived Exosomal miR-301a-3p Regulates Airway Smooth Muscle Cells During Asthma by Targeting STAT3

Abstract

Background Asthma is a chronic inflammatory disease featured by inflammation and remodeling of airway. Adipose-derived mesenchymal stem cell (ADSCs)-derived exosomal miRNAs have been suggested as promising therapeutic manners for diseases. Methods ADSCs and airway smooth muscle cells (ASMCs) were isolated from SD rats. Flow cytometry was conducted to detect the surface biomarkers of isolated cells. Exosomes were extracted by sequentially centrifuge method and identified by Western blotting and nanoparticle tracking analysis (NTA). Uptake of exosomes by ASMCs was detected by confocal assay. ASMCs were treated with platelet-derived growth factor-BB (PDGF-BB) to mimic cell remodeling and inflammation. Cell counting 8 (CCK-8), Transwell, and flow cytometry were performed to determine the viability, migration, and apoptosis of ASMCs. Release of inflammatory factors was detected by enzyme-linked immunosorbent assay (ELISA). Levels of RNAs and proteins were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. Interaction between miR-301a-3p and signal transducer and activator of transcription 3 (STAT3) was determined by luciferase reporter gene assay. The effect of Exosomal miR-301a-3p was analyzed in ovalbumin (OVA)-induced asthma mouse model. Results ADSCs-derived exosomes could be effectively internalized by ASMCs. Exosomal miR-301a-3p notably suppressed the PDGF-BB-stimulated proliferation and migration of ASMCs, and enhanced apoptosis, as well as decreased the secretion of inflammatory factors. MiR-301a-3p directly targeted the 3ʹUTR region of STAT3. STAT3 overexpression reversed the suppressive effects of exosomal miR-301a-3p on ASMCs under PDGF-BB stimulation. The expression of miR-301a-3p and STAT3 was negative correlation in specimen from patients with asthma. Exosomal miR-301a-3p inhibited OVA-induced lung injury by targeting STAT3 in mice. Conclusion This study exposed that exosomal miR-301a-3p from ADSCs could effectively alleviate PDGF-BB-stimulated remodeling and inflammation of ASMCs via targeting STAT3, presented ADSCs-derived exosomal miR-301a-3p as a promising therapeutic approach for asthma.

Noncoding RNAs in asthmatic airway smooth muscle cells

“…Further functional verification found that miR-16-5p inhibits human ASMC proliferation, whereas miR-30d-5p causes an increase in the average cell diameter of human ASMCs [ 62 ]. F eng et al [ 63 ] found that miR-301a-3p decreases in the blood samples from asthma patients and miR-301a-3p directly targets the 3′-UTR region of STAT3, which suppresses the proliferation and migration of ASMCs, enhances ASMC apoptosis and decreases the inflammatory factor secretions of ASMCs. Similarly, miR-335-5p was found to be underexpressed in the plasma of asthmatic children and further results showed miR-335-5p reduces inflammation, airway fibrosis and autophagy in ASMCs [ 64 ].…”

Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools

“…However, they could not differentiate if these effects were associated with exosomes, microvesicles, or a combination of these. In an experiment by Feng et al [ 95 ], the therapeutic potential of AD-MSC-Exo-derived miR-301a-3p was investigated in ovalbumin-induced asthma murine model. They reported that the exosomes were efficiently internalized by airway smooth muscle cells and their secreted miR-301a-3p significantly down-regulated the inflammation, platelet-derived growth factor-BB (PDGF-BB), stimulated proliferation and migration and increased apoptosis in these cells through targeting STAT3.…”

Insights Into the Role of Platelet-Derived Growth Factors: Implications for Parkinson’s Disease Pathogenesis and Treatment

“…(Goetzl et al, 2017) PDGF-BB Exosomal miR-301a-3p derived from adipose-derived mesenchymal stem cellscan lighten remodeling and inflammation of airway smooth muscle cells stimulated by PDGF-BB. (Feng et al, 2022) PDGF-BB Adipose tissue mesenchymal stem cells, bone marrow mesenchymal stem cells, and umbilical cord mesenchymal stem cells secreted exosomes containing PDGF-BB, which can promote keratinocyte and dermal fibroblast proliferation and migration. (Hoang et al, 2020) PDGF-B The exosomes released from astrocytes exerted neurotoxic effects on neurons, which was related to increased miR-29b and decreased PDGF-B expression.…”