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

Chen-Ye Feng; Shi-Yao Bai; Meng-Lu Li; Jie-Yu Zhao; Jia-Min Sun; Hui-Jing Bao; Yuan Ren; Xin-Ming Su

doi:10.2147/JAA.S335680

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

J Asthma Allergy. 2022 Jan 28:15:99-110. doi: 10.2147/JAA.S335680. eCollection 2022.

Authors

Chen-Ye Feng^#¹, Shi-Yao Bai^#¹, Meng-Lu Li¹, Jie-Yu Zhao¹, Jia-Min Sun¹, Hui-Jing Bao¹, Yuan Ren¹, Xin-Ming Su¹

Affiliation

¹ Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University; Respiratory Disease Institution of China Medical University, Shenyang, Liaoning, People's Republic of China.

^# Contributed equally.

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 3'UTR 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.

Keywords: STAT3; asthma; exosome; mesenchymal stem cell; miR-301a-3p.

Grants and funding

This work was supported by projects from The 13th Five-Year Plan National Key R&D Program for Precision Medicine Research (No.: 2016YFC1304500), The National Nature Science of Foundation of China (No.: 81770021).