Exosomes derived from AHR-overexpressing human umbilical cord mesenchymal stem cells attenuate H/R injury via AHR/NLRP3 pathway

Myocardial hypoxia-reoxygenation (H/R) injury is a frequently observed pathological event in various cardiovascular conditions. Despite the therapeutic promise of human umbilical cord mesenchymal stem cells (hUC-MSCs) in alleviating myocardial damage, their clinical use faces obstacles such as limited implantation efficiency, poor retention, and reduced post-transplantation viability. Exosomes secreted by hUC-MSCs have emerged as a viable alternative, potentially addressing these challenges. Nonetheless, the underlying mechanisms through which these exosomes confer cardioprotection have yet to be fully elucidated. This study aims to explore the protective effect of hUC-MSCs exosomes on myocardial H/R injury via the aryl hydrocarbon receptor (AHR)/NOD-like receptor family pyrin domain containing 3 (NLRP3) pathway and to assess their impact on immune cell phenotype conversion. hUC-MSCs exosomes significantly upregulated AHR expression, inhibited NLRP3-related inflammatory protein expression, enhanced myocardial cell survival, and reduced apoptosis. The protective effect of hUC-MSCs exosomes was abolished following AHR knockdown. Additionally, exosomes from AHR-overexpressing hUC-MSCs promoted the conversion of macrophages, dendritic cells (DCs), and T cells to an anti-inflammatory phenotype, thereby further enhancing myocardial protection. These findings indicted that exosomes from AHR-overexpressing hUC-MSCs protect myocardium via AHR/NLRP3 signaling, improving immune microenvironment and offering new therapeutic potential.