Exosomal miR-221-3p Derived from Bone Marrow Mesenchymal Stem Cells Alleviates Asthma Progression by Targeting FGF2 and Inhibiting the ERK1/2 Signaling Pathway

Abstract

Exosomes derived from human bone marrow mesenchymal stem cells (BMSCs) play potential protective roles in asthma. However, the underlying mechanisms remain not fully elucidated. Herein, exosomes were isolated from BMSCs, and the morphology, particle size, and exosome marker proteins were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot, respectively. Then airway smooth muscle cells (ASMCs) were treated with transforming growth factor-β1 (TGF-β1) to construct a proliferation model and then incubated with BMSCs-derived exosomes. We found that exosome incubation increased miR-221-3p expression and inhibited proliferation, migration, and the levels of extracellular matrix (ECM) proteins including fibronectin and collagen III. Moreover, FGF2 was identified as a target gene of miR-221-3p. FGF2 overexpression reversed the inhibitory effects of exosomal miR-221-3p on ASMC progression. Besides, the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) is inhibited by exosomal miR-221-3p, which was reversed by FGF2 overexpression. And ERK1/2 signaling activator reversed the effects of exosomal miR-221-3p on ASMC progression. Additionally, an ovalbumin (OVA)-induced asthmatic mice model was established, and exosome treatment alleviated airway hyper-responsiveness (AHR), histopathological damage, and ECM deposition in asthmatic mice. Taken together, our findings indicated that exosomal miR-221-3p derived from BMSCs inhibited FGF2 expression and the ERK1/2 signaling, thus attenuating proliferation, migration, and ECM deposition in ASMCs and alleviating asthma progression in OVA-induced asthmatic mice. Our findings may provide a novel therapeutic strategy for asthma.

Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement

“…JARID2 is an mRNA target for miR-188 that activates the Wnt/β-catenin signaling pathway 100 . Rat-BM-MSC-derived miR-221-3p suppresses the expression of fibroblast growth factor 2 and the phosphorylation of extracellular signal–regulated kinase 1/2 signaling, thereby inhibiting the proliferation, migration, and ECM deposition of ASMC and alleviating OVA-induced pathological changes in asthmatic mice 101 . Human MSC-EV–derived miR-146a-5p can be taken up by ILC2 and then indirectly regulate Th2 cytokines, leading to the reduction of airway inflammation, mucus secretion, and elimination of AHR 102 .…”