Role of hydrogen peroxide preconditioning in mesenchymal stem cell-mediated heart regeneration: Molecular insights

Mesenchymal stem cells (MSCs) possess unique properties such as immunomodulation, paracrine actions, multilineage differentiation, and self-renewal. Therefore, MSC-based cell therapy is an innovative approach to treating various degenerative illnesses, including cardiovascular diseases. However, several challenges, including low transplant survival rates, low migration to the ischemic myocardium, and poor tissue retention, restrict the application of MSCs in clinical settings. These undesirable cell therapy outcomes mainly originated due to the overproduction of reactive oxygen species (ROS) in the injured heart. MSCs' stress-coping capacity can be enhanced by preconditioning them under conditions similar to the microenvironment of wounded tissues. Hydrogen peroxide (H₂O₂) is a ROS that has been shown to activate protective cellular mechanisms such as survival, proliferation, migration, paracrine effects, and differentiation at sublethal doses. These processes are induced via phosphatidylinositol 3-kinase/protein kinase B, p38 mitogen-activated protein kinases, c-Jun N-terminal kinase, Janus kinase/signal transducer and activator of the transcription, Notch1, and Wnt signaling pathways. H₂O₂ preconditioning could lead to many clinical benefits, including ischemic injury reduction, enhanced survival of cellular transplants, and tissue regeneration. In this review, we present an overview of stem cell preconditioning methods and the biological functions activated by H₂O₂ preconditioning. Furthermore, this review explores the molecular mechanisms underlying the protective cellular functions stimulated under H₂O₂ preconditioning.