Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Aims: Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of induced pluripotent cell-derived cardiomyocytes has been demonstrated, the reported expression of Angiotensin-Converting Enzyme-2 (ACE2) in cardiac stromal cells suggests that SARS-CoV-2 may determine cardiac injury by sustaining productive infection and increasing inflammation. Methods and results: We analysed expression of ACE2 receptor in primary human cardiac stromal cells derived from cardiospheres, using proteomics and transcriptomics before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus release in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production and demonstrated the presence of viral particles in the cells with electron microscopy. We finally used RT-qPCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells after exposure to the virus. Conclusions: Our findings indicate that cardiac stromal cells are susceptible to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved towards hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels. Thus, SARS-CoV-2 infection of myocardial stromal cells could be involved in cardiac injury and explain the high number of complications observed in severe cases of COVID-19. © 2021 Published on behalf of the European Society of Cardiology. All rights reserved.