Mesenchymal stem cell-derived exosomes alleviate post-resuscitation brain injury by inhibiting neuronal ferroptosis partly via the PRMT1/SLC7A11/GPX4 pathway.

Abstract

Background: Post-resuscitation brain injury is the main contributor to the death and disability of cardiac arrest (CA) victims. Neuronal ferroptosis is involved in the pathogenesis of brain injury after resuscitation, which becomes an effective therapeutic target. Recent studies demonstrated that mesenchymal stem cell-derived exosomes (MSC-Exo) were a promising approach for the alleviation of regional cerebral ischemia reperfusion injury; however, its effectiveness in post-resuscitation brain injury remains to be investigated. In this study, we investigated whether MSC-Exo could alleviate post-resuscitation brain injury by inhibiting neuronal ferroptosis and its regulatory mechanism.

Methods and results: In vivo, a clinically relevant swine model of CA and resuscitation was established. In parallel, SH-SY5Y neuronal cells exposed to hypoxia/reoxygenation (H/R) were used as the in vitro model. We found that MSC-Exo administration provided potent protection of neuronal cells against H/R injury in vitro, and effectively alleviated brain injury after CA and resuscitation in vivo. Furthermore, we showed that the protective effects of MSC-Exo administration were associated with the upregulation of protein arginine methyltransferase 1 (PRMT1), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and subsequent inhibition of neuronal ferroptosis in in vitro and in vivo studies. Mechanistically, MSC-Exo administration promoted the recovery of PRMT1 expression, and then the latter bound to the promoter of SLC7A11 and enhanced its transcriptional activity after H/R injury in neuronal cells. Additionally, the miR-320a-3p/tripartite motif-containing 21 (TRIM21) axis was a possible mechanism by which MSC-Exo administration activated the PRMT1/SLC7A11/GPX4 pathway in vitro.

Conclusions: MSC-Exo administration effectively alleviated post-resuscitation brain injury after CA and resuscitation, which was related to the inhibition of neuronal ferroptosis partly through the activation of PRMT1/SLC7A11/GPX4 pathway.