Engineered Exosomes with Growth Differentiation Factor-15 Overexpression Enhance Cardiac Repair After Myocardial Injury

Background: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells.Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury.The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair.Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control.The exosomes secreted from H9C2 cells were collected and identified.The cellular apoptosis and autophagy of H 2 O 2 -injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay.A rat model of AMI was constructed by ligating the left anterior descending artery.The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated.Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment.Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H 2 O 2 injured H9C2 cells.GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI.Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI.RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells.AMPK signaling was activated after GDF15-EVs.Silencing TERT impaired the protective effects of GDF15-EVs on H 2 O 2 -injured H9C2 cells.Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway.GDF15-EVs might be exploited to design new therapies for AMI.