Human Stem Cell Models of SARS-CoV-2 Infection in the Cardiovascular System

Abstract

The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation.

Keywords: COVID-19; Cytokine storm; Heart failure; Human pluripotent stem cells; SARS-CoV-2.

Fig. 1

The structure and genome of the SARS-CoV-2 virus. a The SARS-CoV-2 virion particle consists of the spike (S), envelope (E), nucleocapsid (N), and membrane (M) structural proteins that encase the single-stranded RNA (ssRNA) viral genome. These four proteins play key roles in the processes of viral entry, assembly, and replication. The S protein is required for receptor binding and membrane fusion with the host cell. Once inside the host cell, the N protein serves to package and protect the RNA viral genome into helical ribonucleoprotein complexes. During the viral replication process, E proteins travel to the endoplasmic reticulum and Golgi to assist with virion assembly and budding. Lastly, the M protein functions as an essential mediator for virion assembly and interacts with the S, N, and E proteins to ensure viral retention, stabilization, and envelope formation. b Two-thirds of the SARS-CoV-2 genome at the 5’ terminal end encodes the pp1a and pp1ab polyproteins, which are subsequently cleaved into 16 nonstructural proteins responsible for the replicase complex. The remaining one-third of the genome at the 3’ terminal region encodes the four structural proteins of the virus. The illustration was created with BioRender.com

Fig. 2

The life cycle of the SARS-CoV-2 virus. (1) Cellular entry of SARS-CoV-2 is mediated by binding of the S protein to the host cell’s ACE2 receptor. (2) TMPRSS2 is then responsible for cleavage at the S1/S2 boundary site (“priming”) and the S2 site (“activation”) which facilitates membrane fusion and endocytosis into the host cell. (3) Upon release into the cytoplasm, the first ORF of the viral ssRNA is translated into the pp1a and pp1ab polyproteins. (4) These polyproteins are subsequently processed into non-structural proteins (nsps) that compose the RNA-dependent RNA polymerases (RdRps), which serve to replicate the viral RNA. (5) The viral RNA subsequently becomes translated at the ER and Golgi complex for synthesis of the S, E, N, and M structural proteins. (6) Genomic ssRNA and structural proteins are then packaged into new viral particles, with the M protein functioning as the primary organizer for virion assembly. (7) Once the assembly process is complete, virions will exit the infected host cell through exocytosis. The illustration was created with BioRender.com