Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes

Lu, X. Z.; Rafatian, N.; Zhao, Y.; Wagner, K. T.; Beroncal, E. L.; Li, B.; Lee, C.; Chen, J.; Churcher, E.; Vosoughi, D.; Wang, Y.; Baker, A.; Trahtemberg, U.; Pierro, A.; Andreazza, A.; dos Santos, C. C.; Radisic, M.

doi:10.1101/2023.08.09.552495

bioRxiv · 10.1101/2023.08.09.552495

Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes

Lu, X. Z.·Rafatian, N.·Zhao, Y.·Wagner, K. T.·Beroncal, E. L.·Li, B.·Lee, C.·Chen, J.·Churcher, E.·Vosoughi, D.·Wang, Y.·Baker, A.·Trahtemberg, U.·Pierro, A.·Andreazza, A.·dos Santos, C. C.·Radisic, M.

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Abstract

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.

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Lu, X. Z., Rafatian, N., Zhao, Y., Wagner, K. T., Beroncal, E. L., Li, B., Lee, C., Chen, J., Churcher, E., Vosoughi, D., Wang, Y., Baker, A., Trahtemberg, U., Pierro, A., Andreazza, A., dos Santos, C. C., Radisic, M.. 2023-08-09. Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes. https://doi.org/10.1101/2023.08.09.552495

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