Faculty Collaboration Database

SARS-CoV-2 pathogenesis in an angiotensin II-induced heart-on-a-chip disease model and extracellular vesicle screening. Proc Natl Acad Sci U S A 2024 Jul 09;121(28):e2403581121

Date

07/05/2024

Pubmed ID

38968108

Pubmed Central ID

PMC11253010

DOI

10.1073/pnas.2403581121

Scopus ID

2-s2.0-85197801239 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

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.

Author List

Wu Q, Rafatian N, Wagner KT, Blamer J, Smith J, Okhovatian S, Aggarwal P, Wang EY, Banerjee A, Zhao Y, Nash TR, Lu RXZ, Portillo-Esquivel LE, Li CY, Kuzmanov U, Mandla S, Virlee E, Landau S, Lai BF, Gramolini AO, Liu C, Fleischer S, Veres T, Vunjak-Novakovic G, Zhang B, Mossman K, Broeckel U, Radisic M

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Apoptosis
Cytokines
Extracellular Vesicles
Humans
Induced Pluripotent Stem Cells
Lab-On-A-Chip Devices
MicroRNAs
Myocytes, Cardiac