Hypoxic mesenchymal stem cell-derived exosomes alleviate ulcerative colitis injury by limiting intestinal epithelial cells reactive oxygen species accumulation and DNA damage through HIF-1α

Abstract

Ulcerative colitis (UC) is an inflammatory disease with a complex pathogenic mechanism. Mounting evidence suggests that UC pathogenesis is linked to excessive production of reactive oxygen species (ROS) and cellular DNA damage. Recent studies have shown that bone mesenchymal stem cells (BMSCs) mainly exert their therapeutic effects through paracrine exosomes, and oxygen concentration is extremely important to BMSCs and exosomes. The main objective of this study was to determine whether exosomes from BMSCs under hypoxic conditions (HP-Exos) exhibit a greater therapeutic effect on UC compared to exosomes under normoxic conditions (Exos) and to resolve the mechanism of HP-Exos. We observed that hypoxia enhances the activity and migration of BMSCs and inhibits BMSC apoptosis without changing their morphological characteristics. Furthermore, HP-Exos significantly relieved UC symptoms and pathological damage. In order to further understand the mechanism of HP-Exos in UC, findings from in vivo experiments demonstrated that HP-Exos reduces ROS production, DNA damage and apoptosis in intestinal epithelial cells. As hypoxia-inducible factor 1α (HIF-1α) plays an important role in hypoxia, we knocked down HIF-1α in BMSCs. HIF-1α knockout reversed the effects of hypoxia on the activity, migration and apoptosis of BMSCs. Moreover, inhibition of HIF-1α expression also reversed the regulation of UC by HP-Exos. Therefore, we conclude that HP-Exos regulates ROS accumulation, DNA damage and immune homeostasis in intestinal epithelial cells via HIF-1α.

Keywords: Exosomes; HIF-1α; Hypoxic; ROS; Ulcerative colitis.