SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.
SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.
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DOI：
10.1161/circresaha.121.320518
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发表时间：
2022-04
影响因子：
20.1
通讯作者：
Chen S
中科院分区：
文献类型：
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作者：
Han Y;Zhu J;Yang L;Nilsson-Payant BE;Hurtado R;Lacko LA;Sun X;Gade AR;Higgins CA;Sisso WJ;Dong X;Wang M;Chen Z;Ho DD;Pitt GS;Schwartz RE;tenOever BR;Evans T;Chen S
越来越多的证据表明，心律失常是COVID-19的常见临床特征。窦房结损伤可能导致心动过缓。然而，由于难以分离和培养人窦房结（SAN）细胞，因此探索人SAN的病理生理具有挑战性。胚胎干细胞（ESCs）可以作为一种来源，衍生人类SAN样起搏细胞用于疾病建模。我们使用仓鼠模型和hESC衍生的SAN样起搏细胞来探索SARS-CoV-2感染对心脏起搏细胞的影响。在仓鼠模型中，分别使用qRT-PCR和免疫染色检测病毒RNA和蛋白。然后，我们创建了双敲入SHOX 2：GFP; MYH 6：mCherry hESC报告细胞系，以建立一种高效的策略来获得功能性人SAN样起搏细胞，并通过单细胞RNA-seq对其进行了进一步表征。在暴露于SARS-CoV-2后，使用qRT-PCR、免疫染色和RNA-seq来确认感染并确定hESC-SAN样起搏细胞的宿主反应。最后，进行高含量的化学筛选以鉴定可以抑制SARS-CoV-2感染和阻断SARS-CoV-2诱导的铁凋亡的药物。在感染仓鼠心脏的SAN细胞中检测到病毒RNA和刺突蛋白。我们建立了一种有效的策略，从hESC中获得功能性人SAN样起搏细胞，其表达起搏标记物并显示SAN样动作电位。此外，SARS-CoV-2感染导致人类SAN样起搏细胞功能障碍并诱导铁凋亡。从高含量筛选中鉴定出两种候选药物，去铁胺和伊马替尼，能够阻断SARS-CoV-2感染和感染相关的铁凋亡。使用仓鼠模型，我们发现心脏中的初级起搏细胞可以被SARS-CoV-2感染。hESC衍生的功能性SAN样起搏细胞的感染证明了铁凋亡是COVID-19患者引起心律失常的潜在机制。最后，我们确定了可以保护SAN细胞免受SARS-CoV-2感染的候选药物。
Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of 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. We used both a hamster model and hESC-derived SAN-like pacemaker cells to explore the impact of SARS-CoV-2 infection on the pacemaker cells of the heart. In the hamster model, qRT-PCR and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA-seq. Following exposure to SARS-CoV-2, qRT-PCR, immunostaining and RNA-seq were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2 induced ferroptosis. Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in COVID-19 patients. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.