SARS- CoV-2 pathogenesis in an angiotensin II-induced heart- on- a- chip disease model and extracellular vesicle screening

• 成果类型: Article
• 署名作者: Wu, Qinghua; Rafatian, Naimeh; Wagner, Karl T.; Blamer, Jacob; Smith, Jacob; Okhovatian, Sargol; Aggarwal, Praful; Wang, Erika Yan; Banerjee, Arinjay; Zhao, Yimu; Nash, Trevor R.; Lu, Rick Xing Ze; Portillo-Esquivel, Luis Eduardo; Li, Chen Yu; Kuzmanov, Uros; Mandla, Serena; Virlee, Elizabeth; Landau, Shira; Black, Lauren D.; Griffin, Diane E.; Lai, Benjamin Fook; Gramolini, Anthony O.; Liu, Chuan; Fleischer, Sharon; Veres, Teodor; Vunjak-Novakovic, Gordana; Zhang, Boyang; Mossman, Karen; Broeckel, Ulrich; Radisic, Milica
• 署名单位: University of Toronto; University of Toronto; University Health Network Toronto; Toronto General Hospital; University of Toronto; University of Toronto; Medical College of Wisconsin; McMaster University; University of Saskatchewan; Columbia University; McMaster University; University of Toronto; University of Toronto; National Research Council Canada; University of Toronto; Columbia University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14175
• DOI: 10.1073/pnas.2403581121
• 发表日期: 2024-07-09
• 关键词: cardiomyocyte apoptosis; hypertrophy; receptor; FAILURE; cells

摘要

Adverse cardiac outcomes in COVID- 19 patients, particularly those with preexisting cardiac disease, motivate the development of human cell- based organ- on- a- chip models to recapitulate cardiac injury and dysfunction and for screening of cardioprotective therapeutics. Here, we developed a heart- on- a- chip model to study the pathogenesis of SARS- CoV- 2 in healthy myocardium established from human induced pluripotent stem cell (iPSC)- derived cardiomyocytes and a cardiac dysfunction model, mimicking aspects of preexisting hypertensive disease induced by angiotensin II (Ang II). We recapitulated cytopathic features of SARS- CoV- 2- induced cardiac damage, including progressively impaired contractile function and calcium handling, apoptosis, and sarcomere disarray. SARS- CoV- 2 presence in Ang II- treated hearts- on- a- chip decreased contractile force with earlier onset of contractile dysfunction and profoundly enhanced inflammatory cytokines compared to SARS- CoV- 2 alone. Toward the development of potential therapeutics, we evaluated the cardioprotective effects of extracellular vesicles (EVs) from human iPSC which alleviated the impairment of contractile force, decreased apoptosis, reduced the disruption of sarcomeric proteins, and enhanced beta- oxidation gene expression. Viral load was not affected by either Ang II or EV treatment. We identified MicroRNAs miR- 20a- 5p and miR- 19a- 3p as potential mediators of cardioprotective effects of these EVs.