Mesenchymal stem cells alleviate epithelial-to-mesenchymal transition by modulating the IRE1α branch of the endoplasmic reticulum stress response

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease, and it carries a poor prognosis due to the lack of efficient diagnosis and treatments. Epithelial-mesenchymal transition (EMT) plays a key role in the pathogenesis of IPF. Endoplasmic reticulum (ER) stress contributes to fibrosis via EMT-mediated pathways. Mesenchymal stem cells (MSCs) are a promising treatment for pulmonary fibrosis and ameliorate lung fibrosis via paracrine effects in animal models. However, the specific mechanisms are not known. We previously reported that MSCs attenuated endothelial injury by modulating ER stress and endothelial-to-mesenchymal transition (EndMT). The present investigated whether modulation of ER stress and EMT-related pathways played essential roles in MSC-mediated alleviation of IPF.Methods and results: We constructed a transforming growth factor-β1 (TGF-β1)-induced fibrosis model in A549 cells. TGF-β1 induced EMT in A549 cells, and MSC coculture ameliorated EMT, which was characterized by increased E-cadherin and decreased vimentin levels. ER stress participated in TGF-β1-induced EMT in A549 cells, and MSCs inhibited the expression of XBP-1s XBP-1u and BiP, which were upregulated by TGF-β1. Inhibition of ER stress contributed to MSC-mediated amelioration of EMT in A549 cells, in which modulation of the IRE1α-XBP1 branch of the ER stress pathway may play an important role. MSC transplantation alleviated bleomycin-induced pulmonary fibrosis in mice. MSC treatment decreased the expression of ER stress- and EMT-related genes and proteins, and inhibition of the IRE1α/XBP1 pathway was the most obvious effect.Conclusions: The present study demonstrated that MSCs alleviated EMT by modulating ER stress and blockade of the IRE1α-XBP1 pathway may play a critical role. The current study provides a novel vision for the application of MSCs for IPF treatment and elucidates the mechanism of the preventive effects of MSCs against pulmonary fibrosis.