Extracellular vesicles derived from HuMSCs alleviate daunorubicin-induced cardiac microvascular injury via miR-186-5p/PARP9/STAT1 signal pathway

It is essential to acknowledge the long-term cardiovascular toxicity associated with anthracycline drugs, which can be partially attributed to the harm inflicted on endothelial cells. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have the potential to repair cellular processes and promote tissue regeneration through the transfer of signaling molecules such as miRNAs. In the present study, we investigated the effects of MSC-EVs on daunorubicin (DNR)-damaged human cardiac microvascular endothelial cells (HCMEC). We found that MSC-EVs improved the migration, proliferation, and angiogenesis of HCMEC, while also alleviating cellular senescence. Through RNA sequencing analysis and RNA interference experiments, we identified that MSC-EVs downregulated the expression of PARP9, thereby inhibiting the STAT1/pSTAT1 signaling pathway. This downregulation effect is likely mediated by the transfer of miR-186-5p from MSC-EVs to HCMEC. Overexpression of miR-186-5p in DNR-damaged HCMEC also exhibited the aforementioned downregulation effect. In conclusion, our study reveals that MSC-EVs can restore the cellular function of DNR-damaged HCMEC and alleviate cellular senescence through the miR-185-5p-PARP9-STAT1/pSTAT1 pathway. This finding highlights the potential of MSC-EVs as a therapeutic strategy for mitigating the detrimental effects of anthracycline-induced cellular damage. Overall design: RNA sequencing was performed on the following three groups of human cardiac microvascular endothelial cells, including: the Blank group, the DNR-damaged group, and the DNR-damaged + MSC-EVs group. Two replicates were performed for each group.