Heart-on-a-chip model of SARS-CoV-2 infection and treatment with induced pluripotent stem cell derived extracellular vesicles

Abstract: Although COVID-19–associated heart dysfunction has identified in individuals with SARS-CoV-2 infection, complex and multifaceted pathophysiology in patients complicates the investigation of pathogenesis related to clinical manifestations and mechanisms of cardiac dysfunction after viral invasion. This study comprehensively investigated pathogenesis regarding SARS-CoV-2 infection via tissue model established from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiomyopathy model induced by angiotensin II. We recapitulated cytopathic features of SARS-CoV-2-induced cardiac damage and monitored the course of cardiac complications after infection, which is critically important to develop therapeutics. We found that SARS-CoV-2 infection of hiPSC-CMs models progressively impaired contractile function and calcium handling and led to cell death. Therapeutics potential towards myocardial injury was further developed in our tissue model. We evaluated cardioprotective effects of extracellular vesicles (EVs) derived from hiPSC source on the infected tissues, indicating that EVs alleviated the impairment of contractile force and cardiac cell death following SARS-CoV-2 infection. We showed that enriched microRNA in hiPSC-EVs can modulate cardiac-specific processes. These findings suggested that cardiac manifestations examined from tissues models provided insights into cardiac injury induced by SARS-CoV-2 infection, and model systems allow the investigation of mechanisms driving cardiac dysfunction and iPSC-EVs served as a promising therapy to rescue cardiac damage from infection. Overall design: Gene expression profiles of engineered human cardiomyocytes untreated (Control) and treated with SARS-Cov-2 (MOI5), iPSC-derived extracellular vescicles (MOI5-EV), and/or angiotensin II (Ang II)