Targeting ER stress-mediated apoptosis by MSC-derived exosomes: A novel therapeutic strategy against pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is marked by a gradual decline in pulmonary function over time and is associated with a grim prognosis. In the pathogenesis of IPF, persistent endoplasmic reticulum (ER) stress plays a significant role in promoting fibrosis through pathways involving apoptosis. Mesenchymal stem cell-derived exosomes (MSC-Ex) have shown promise in mitigating pulmonary fibrosis by inhibiting apoptosis. Nonetheless, the precise mechanisms underlying this effect remain unclear. In our previous findings, we demonstrated that MSCs alleviate pulmonary fibrosis by regulating ER stress. Building upon this, we sought to investigate whether MSC-Ex could mitigate alveolar epithelial cell apoptosis through the ER stress pathway. We posited that targeting ER stress could represent a crucial mechanism by which MSC-Ex alleviate apoptosis in IPF models. METHODS AND RESULTS: In this study, bleomycin (BLM) induced apoptosis in A549 cells, and MSC-Ex treatment reduced apoptotic cells and the Bax/Bcl-2 ratio. ER stress is involved in BLM-induced apoptosis in A549 cells, and MSC-Ex reduced ER stress-related protein (Bip and CHOP) expression and reversed the morphological changes of the ER in A549 cells. Moreover, blockade of ER stress with ER stress inhibitor TUDCA contributed to the amelioration of apoptosis in A549 cells, indicating that MSC-Ex reduced BLM-induced apoptosis at least partly by modulating ER stress. In vivo, MSC-Ex injection decreased BLM-induced pulmonary fibrosis in mice, as well as ER stress and apoptosis in the lung tissues. CONCLUSIONS: In conclusion, ER stress induced apoptosis in BLM-treated A549 cells, and MSC-Ex treatment mitigated apoptosis via inhibiting ER stress. This study provides a novel mechanism for MSC-Ex-mediated protection on apoptosis in an IPF model and suggests that MSC-Ex could be a promising therapeutic strategy for IPF.