iPSC-MSC-derived exosomes attenuate pulmonary fibrosis by inhibiting pulmonary fibroblast activation via delivery of TRIM31.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a serious and progressive lung disease characterized by devastating and progressive fibrosis. Treatment is unsatisfactory. There is accumulating evidence that transplantation of mesenchymal stem cell derived exosomes (MSC-EXOs) protects against IPF. This study aimed to investigate the protective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSC-EXOs) on pulmonary fibrosis and explore the underlying mechanisms. Exosomes were isolated from bone marrow-MSCs (BM-MSCs) and iPSC-MSCs and subsequently identified. A mouse model of pulmonary fibrosis was established by tracheal injection of bleomycin (BLM) followed by transplantation of BM-MSC-EXOs or iPSC-MSC-EXOs via tail vein injection. Pulmonary function and fibrosis were assessed by pulmonary function tests (PFT) and Masson trichrome staining, respectively. Mice lung fibroblasts (LFs) were treated with BM-MSC-EXOs or iPSC-MSC-EXOs in the presence of TGF-β1 in vitro. Compared with BM-MSC-EXOs, iPSC-MSC-EXO treatment significantly enhanced pulmonary function and decreased the fibrosis and lactate level in a mouse model of BLM-induced pulmonary fibrosis. In vitro, iPSC-MSC-EXOs exerted a superior protective efficacy against TGF-β1-induced LF activation via downregulation of the lactate level. Further analysis revealed a higher protein level of TRIM31 in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, exosomal TRIM31 from iPSC-MSC-EXOs inhibited LF activation via downregulation of glycolysis by mediating ubiquitination of hexokinase 2 (HK2). Furthermore, knockdown of TRIM31 reduced the protective effects of iPSC-MSC-EXOs on pulmonary fibrosis in BLM-treated mice. Our study showed that TRIM31 delivered by iPSC-MSC-EXOs exerted anti-pulmonary fibrotic effects by alleviating LF activation via regulation of HK2 ubiquitination. This study provides a potential therapeutic strategy for patients with IPF.