Detection of Synthetic Viral RNA Fragments in Human iPSC-Cardiomyocytes following Treatment with Precipitated Extracellular Vesicles from SARS-CoV-2 Coding-Sequence-Overexpressing Lung Epithelial Cells

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a worldwide pandemic. Early data suggest that the prevalence and severity of COVID-19 appear to be higher among patients with underlying cardiovascular risk factors. Despite the expression of angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV-2 infection, in cardiomyocytes, there has been no evidence of direct viral infection although the presence of inflammation and viral genome within the hearts of COVID-19 patients have been reported. Here we transduced A549 lung epithelial cells with lentivirus overexpressing selected genes of the SARS-CoV-2. We then isolated exosomes from the supernatant of A549 cells and detected the presence of viral genome within the purified exosomes. Importantly, we observed that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were able to actively uptake these exosomes and viral genes were subsequently detected in the cardiac cells. Accordingly, uptake of exosomes containing viral genes led to an upregulation of inflammation-related genes in hiPSC-CMs. Thus, our findings indicate that SARS-CoV-2 RNA-containing exosomes represent an indirect route of entry into cardiomyocytes resulting in potential cardiac dysfunction without the need for direct viral infection.