Background: Stem cell therapy is a promising treatment to restore the injured myocardium; however, little is known about the underlying repair mechanism. The injured murine myocardium treated with human-placenta-derived amniotic mesenchymal stem cells (hAMSCs), situated at the maternal-fetal interface, produce anti-apoptotic, anti-fibrotic, anti-inflammatory and pro-angiogenic cytokines to restore the injured myocardium. We propose that these pleiotropic effects are modulated by exosomes, which are enriched in cardioprotective microRNAs to regulate the protein translation in the local population of cardiomyocytes to repair the injured but viable myocardium. Methods: hAMSCs were isolated from human placental amniotic membrane. Exosomes from the hAMSC supernatant were isolated by PEG incubation and centrifugation, then verified by CD63 immunoblotting, NanoSight and dynamic light scattering analyses. MicroRNA content of hAMSC exosomes was determined through quantitative reverse-transcriptase PCR analysis. SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and injected with hAMSC exosomes in the peri-infarct region, n=9 (2 exosomes and 7 control). Cardiac MRI assessed myocardial viability and left ventricular ejection function (LVEF) 4 weeks postinjection. Results: hAMSC exosomes have a diameter of 30-80 nm and are enriched in microRNAs that are up-regulated during cardiac injury (miR- 15a, miR-20b, miR-21). SCID mice treated with hAMSC exosomes compared to the control had significantly improved LVEF (37.4±7.3% vs. 19.8±5.73%, p<0.01) and % myocardial viability (78.7±1.34% vs. 46.0±8.41%, p<0.01). Conclusions: Myocardial restoration after MI is enhanced by exogenous administration of cardioprotective miRNAs, which are transferred to the injured cardiomyocytes by the hAMSC exosomes. This study provides initial insights into a novel cell-free delivery system of therapeutic agents for cardiac injury.
Santoso, M., Mahmoudi, M., Tachibana, A., Sierra, R. G., Matsui, T., Goldstone, A., … Yang, P. (2016). EXOSOMES FROM THE HUMAN PLACENTA-DERIVED AMNIOTIC MESENCHYMAL STEM CELLS RESTORE THE INJURED MURINE MYOCARDIUM. Journal of the American College of Cardiology, 67(13), 1393. https://doi.org/10.1016/s0735-1097(16)31394-8