Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes.

Publication date: Mar 29, 2024

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)-induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, 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 endothelial cell-derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor-nuclear factor _705B signaling axis.

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Concepts Keywords
Bioengineered Acute
Cardiac Cardiac
Coronavirus Cell
Free Chip
Nuclear Circulating
Dysfunction
Exosomes
Free
Heart
Immune
Induced
Inflammation
Mitochondrial
Models
Myocardial

Semantics

Type Source Name
disease IDO cell
disease MESH inflammation
disease VO Severe acute respiratory syndrome coronavirus 2
disease MESH myocarditis
pathway KEGG Coronavirus disease
disease MESH COVID-19
drug DRUGBANK Calcium
pathway REACTOME Release
disease VO Toll-like receptor

Original Article

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