tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2024 Jul 9;121(28):e2403581121.
doi: 10.1073/pnas.2403581121. Epub 2024 Jul 5. SARS-CoV-2 pathogenesis in an angiotensin II-induced heart-on-a-chip disease model and extracellular vesicle screening
Qinghua Wu[SUP] 1 2 [/SUP], Naimeh Rafatian[SUP] 1 [/SUP], Karl T Wagner[SUP] 1 3 [/SUP], Jacob Blamer[SUP] 4 [/SUP], Jacob Smith[SUP] 3 [/SUP], Sargol Okhovatian[SUP] 1 2 [/SUP], Praful Aggarwal[SUP] 4 [/SUP], Erika Yan Wang[SUP] 1 [/SUP], Arinjay Banerjee[SUP] 5 6 [/SUP], Yimu Zhao[SUP] 7 [/SUP], Trevor R Nash[SUP] 7 [/SUP], Rick Xing Ze Lu[SUP] 1 [/SUP], Luis Eduardo Portillo-Esquivel[SUP] 8 [/SUP], Chen Yu Li[SUP] 3 [/SUP], Uros Kuzmanov[SUP] 9 10 [/SUP], Serena Mandla[SUP] 2 [/SUP], Elizabeth Virlee[SUP] 4 [/SUP], Shira Landau[SUP] 1 [/SUP], Benjamin Fook Lai[SUP] 1 [/SUP], Anthony O Gramolini[SUP] 9 10 [/SUP], Chuan Liu[SUP] 1 2 11 [/SUP], Sharon Fleischer[SUP] 7 [/SUP], Teodor Veres[SUP] 12 13 [/SUP], Gordana Vunjak-Novakovic[SUP] 7 14 [/SUP], Boyang Zhang[SUP] 8 [/SUP], Karen Mossman[SUP] 5 [/SUP], Ulrich Broeckel[SUP] 4 [/SUP], Milica Radisic[SUP] 1 2 3 11 [/SUP]
Affiliations
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.
Keywords: SARS-CoV-2; cardiomyocyte; induced pluripotent stem cell; myocardium; organ-on-a-chip.
. 2024 Jul 9;121(28):e2403581121.
doi: 10.1073/pnas.2403581121. Epub 2024 Jul 5. SARS-CoV-2 pathogenesis in an angiotensin II-induced heart-on-a-chip disease model and extracellular vesicle screening
Qinghua Wu[SUP] 1 2 [/SUP], Naimeh Rafatian[SUP] 1 [/SUP], Karl T Wagner[SUP] 1 3 [/SUP], Jacob Blamer[SUP] 4 [/SUP], Jacob Smith[SUP] 3 [/SUP], Sargol Okhovatian[SUP] 1 2 [/SUP], Praful Aggarwal[SUP] 4 [/SUP], Erika Yan Wang[SUP] 1 [/SUP], Arinjay Banerjee[SUP] 5 6 [/SUP], Yimu Zhao[SUP] 7 [/SUP], Trevor R Nash[SUP] 7 [/SUP], Rick Xing Ze Lu[SUP] 1 [/SUP], Luis Eduardo Portillo-Esquivel[SUP] 8 [/SUP], Chen Yu Li[SUP] 3 [/SUP], Uros Kuzmanov[SUP] 9 10 [/SUP], Serena Mandla[SUP] 2 [/SUP], Elizabeth Virlee[SUP] 4 [/SUP], Shira Landau[SUP] 1 [/SUP], Benjamin Fook Lai[SUP] 1 [/SUP], Anthony O Gramolini[SUP] 9 10 [/SUP], Chuan Liu[SUP] 1 2 11 [/SUP], Sharon Fleischer[SUP] 7 [/SUP], Teodor Veres[SUP] 12 13 [/SUP], Gordana Vunjak-Novakovic[SUP] 7 14 [/SUP], Boyang Zhang[SUP] 8 [/SUP], Karen Mossman[SUP] 5 [/SUP], Ulrich Broeckel[SUP] 4 [/SUP], Milica Radisic[SUP] 1 2 3 11 [/SUP]
Affiliations
- PMID: 38968108
- DOI: 10.1073/pnas.2403581121
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.
Keywords: SARS-CoV-2; cardiomyocyte; induced pluripotent stem cell; myocardium; organ-on-a-chip.