A novel mechanism underlying the immunomodulation effects of mesenchymal stem cell-exosomes for cardiac repair

Mesenchymal stem cell-exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes.

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 in cardiac-draining mediastinal lymph node. Then by using NonTomy MI models, mesenchymal stem cell-exosomes or vehicle PBS was intrapericardially injected for MI treatment. After detection of exosome distribution, cell sorting and RNA-seq, the differentially expressed genes were acquired for integrated pathway analysis to identify responsible factors. Further through functional knockdown/inhibition studies, application of cytokines and neutralizing antibodies, western blot, flow cytometry, and cytokine array, the molecular mechanism was investigated. In addition, the therapeutic efficacy of intrapericardially injected exosomes for MI treatment was evaluated through functional and histological analysis.

North Carolina State University researchers show that pericardial draining pathway promoted immune activation in the mediastinal lymph node following MI. Intrapericardially injected exosomes accumulated in the mediastinal lymph node and induced regulatory T cell differentiation to promote cardiac repair. Mechanically, uptake of exosomes by MHC-II⁺ antigen-presenting cells induced Foxo3 activation via PP2A/p-Akt/Foxo3 pathway. Foxo3 dominated antigen-presenting cell cytokines (IL-10, IL-33, and IL-34) expression and built up a regulatory T cell-inducing niche in the mediastinal lymph node. The differentiation of regulatory T cells as well as their cardiac deployment were elevated, which contributed to cardiac inflammation resolution and cardiac repair.

This study reveals a novel mechanism underlying the immunomodulation effects of mesenchymal stem cell-exosomes and provides a promising candidate (PP2A/p-Akt/Foxo3 signal pathway) with a preferred delivery route (intrapericardial injection) for cardiac repair.