SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis


Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia.

However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.

The sinoatrial node (SAN) is the primary pacemaker of the heart and controls heart rate throughout life. Failure of SAN function due to congenital disease or aging results in slowing of the heart rate and inefficient blood circulation, a condition treated by implantation of an electronic pacemaker.

The ability to produce pacemaker cells in vitro could lead to an alternative, biological pacemaker therapy in which the failing SAN is replaced through cell transplantation. Here we describe a transgene-independent method for the generation of SAN-like pacemaker cells (SANLPCs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways. SANLPCs are identified as NKX2-5 cardiomyocytes that express markers of the SAN lineage and display typical pacemaker action potentials, ion current profiles and chronotropic responses. When transplanted into the apex of rat hearts, SANLPCs are able to pace the host tissue, demonstrating their capacity to function as a biological pacemaker.

reference link :,implantation%20of%20an%20electronic%20pacemaker.

The study findings were published in the peer reviewed journal: Circulation Research by AHA (American Heart Association).

The sinoatrial node (SAN) represents the primary pacemaker of the heart, situated at the junction of the right atrium and the right common cardinal vein, controlling cardiac rhythm through the downstream components of the cardiac conduction system.

It has, however, been challenging to model SAN damage in mammals due to the lack of protocols to isolate and culture SAN cells. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), provide a viable strategy to derive functional human SAN-like pacemaker cells.

Progress has been made to derive SAN-like pacemaker cells from hESC/hiPSC by directed differentiation,1 nodal inhibition,2 and overexpression of TBX33 or TBX18.4 However, most of these reports either use an NKX2.5 negative selection approach to enrich nodal-like cells or no selection.

To generate a positive selection tool, we created a dual knock-in SHOX2:GFP; MYH6:mCherry reporter line using CRISPR/Cas-based gene-targeting techniques that facilitate the quantification and purification of SAN-like pacemaker cells.

We used this reporter to develop an efficient strategy to derive functional SAN-like pacemaker cells from hPSCs, which can be applied for disease modeling and drug screening.

Cardiac arrhythmias have been reported in nearly 17% of hospitalized patients with coronavirus disease 2019 (COVID-19), which is associated with a worse disease prognosis.

A recent review 5 suggested that supraventricular tachycardia is the most commonly seen electrocardiogram abnormality, which can have many causes including hypoperfusion, electrolyte abnormalities, or anxiety. In addition, sinus bradycardia, a frequent clinical feature of COVID-19, is observed in 56% of hospitalized febrile patients.6,7

Additional case studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to induce a transient sinus bradycardia in some patients with COVID-19.8 A retrospective study in Japan showed that relative bradycardia was a common characteristic for 54 patients with polymerase chain reaction (PCR)-confirmed mild-to-moderate COVID-19.9

Moreover, it was reported that one-third of patients with severe illness developed sinus bradycardia even with no severe myocardial damage or cardiac insufficiency,6,10 suggesting that there might be an independent cause of sinus bradycardia in patients with COVID-19.

Sinus node damage may lead to bradycardia. No reports exist so far documenting whether the SAN can be infected by SARS-CoV-2 in patients with COVID-19. This can only be determined by biopsy or autopsy and is controversial even for the myocardium.

However, postmortem tissues from patients with COVID-19 only evaluate the end-stage of infection, which might not reflect the initial response after acute infection. Therefore, we used a combination of an in vivo hamster model and hESC-SAN–like pacemaker cells to systematically study the impact of SARS-CoV-2 infection on the SAN.

Syrian golden hamsters (Mesocricetus auratus) are an established highly susceptible preclinical animal model for SARS-CoV-2 infection.11–14 Indeed, cardiovascular related complications have been demonstrated in SARS-CoV-2–infected hamsters.15 We systematically examined the SAN tissue of SARS-CoV-2–infected hamsters and detected viral protein and double-stranded RNA (dsRNA) in HCN4+ (hyperpolarization activated cyclic nucleotide gated potassium channel 4) SAN cells in vivo. Finally, we found that SARS-CoV-2 infection induced ferroptosis of human SAN-like pacemaker cells and identified drugs that can block SARS-CoV-2 infection and ferroptosis.


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