Intrapericardial injection of MSC exosomes promoted cardiac repair and inflammation resolution in a myocardial infarction model by activating the PP2A/p-Akt/Foxo3 pathway in antigen-presenting cells.
Does intrapericardial injection of MSC-derived exosomes improve cardiac repair in myocardial infarction models?
Intrapericardial delivery of MSC exosomes promotes cardiac repair after myocardial infarction by activating the Foxo3 pathway and enhancing regulatory T cell deployment.
BACKGROUND: Mesenchymal stem cell (MSC)-derived exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. The Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes. METHODS: Myocardial infarction (MI) models with and without pericardiectomy (corresponding to Tomy MI and NonTomy MI) were established to study the functions of pericardial drainage pathway in immune activation of cardiac-draining mediastinal lymph node (MLN). Using the NonTomy MI model, MSC exosomes or vehicle PBS was intrapericardially injected for MI treatment. Via cell sorting and RNA-seq (RNA-sequencing) analysis, the differentially expressed genes were acquired for integrated pathway analysis to identify responsible mechanisms. Further, through functional knockdown/inhibition studies, application of cytokines and neutralizing antibodies, western blot, flow cytometry, and cytokine array, the molecular mechanisms were studied. In addition, the therapeutic efficacy of intrapericardially injected exosomes for MI treatment was evaluated through functional and histological analyses. RESULTS: antigen-presenting cells (APCs) induced Foxo3 activation via the protein phosphatase (PP)-2A/p-Akt/forkhead box O3 (Foxo3) pathway. Foxo3 dominated APC cytokines (IL-10, IL-33, and IL-34) expression and built up a regulatory T cell (Treg)-inducing niche in the MLN. The differentiation of Tregs as well as their cardiac deployment were elevated, which contributed to cardiac inflammation resolution and cardiac repair. CONCLUSIONS: This study reveals a novel mechanism underlying the immunomodulation effects of MSC exosomes and provides a promising candidate (PP2A/p-Akt/Foxo3 signaling pathway) with a favorable delivery route (intrapericardial injection) for cardiac repair.
Zhu et al. (Thu,) conducted a other in Myocardial infarction. MSC exosomes (intrapericardially injected) vs. Vehicle PBS was evaluated on Cardiac repair and immunomodulation (Foxo3 activation, Treg differentiation). Intrapericardial injection of MSC exosomes promoted cardiac repair and inflammation resolution in a myocardial infarction model by activating the PP2A/p-Akt/Foxo3 pathway in antigen-presenting cells.