SARS-CoV2 infection of iPSC-derived cardiac cells predicts novel cytopathic features in COVID-19 patientsÂ

Mounting clinical evidence indicates severe pathological consequences from COVID-19 in the heart. Here we examine cardiac susceptibility and response to SARS-CoV-2 using human induced pluripotent stem cell-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells. Of these cell types, SARS-CoV-2 can only productively infect cardiomyocytes, and does so via an endolysosomal mechanism. Transcriptomic profiling of infected cells revealed changes in protein homeostasis and cardiomyocyte contractility, and activation of innate immune response pathways. In addition, we observed a striking pattern of myofibrillar fragmentation, with specific cleavage at the M-line. Numerous cardiomyocytes also lacked nuclear DNA in tissue culture experiments and COVID-19 autopsy specimens. These novel cardiac pathologies induced by SARS-CoV-2 strongly motivate the development of targeted cardioprotective strategies to prevent acute and long-term heart failure in COVID-19 patients.

不断积累的临床证据表明，新冠病毒（COVID-19）感染可对心脏造成严重病理后果。本研究利用人类诱导多能干细胞（human induced pluripotent stem cell）分化的心肌细胞（cardiomyocytes）、心脏成纤维细胞（cardiac fibroblasts）与内皮细胞（endothelial cells），探究了心脏对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的易感性与应答反应。在上述细胞类型中，SARS-CoV-2仅能在心肌细胞中实现产毒性感染，且该过程依赖内溶酶体途径（endolysosomal mechanism）。对感染细胞的转录组分析显示，其蛋白质稳态（protein homeostasis）与心肌细胞收缩功能出现异常，同时固有免疫应答通路被激活。此外，我们还观察到一种显著的肌原纤维（myofibrillar）断裂模式，其特定位点切割发生在M带（M-line）处。在组织培养实验与新冠患者尸检样本中，大量心肌细胞还存在核DNA缺失的现象。SARS-CoV-2诱导的上述新型心脏病理改变，有力地推动了靶向心脏保护策略的研发，以预防新冠患者出现急性与长期心力衰竭。