TY - JOUR
AU - Rick Xing Ze Lu
AU - Naimeh Rafatian
AU - Yimu Zhao
AU - Karl T. Wagner
AU - Erika L. Beroncal
AU - Bo Li
AU - Carol Lee
AU - Jingan Chen
AU - Eryn Churcher
AU - Daniel Vosoughi
AU - Chuan Liu
AU - Ying Wang
AU - Andrew Baker
AU - Uriel Trahtemberg
AU - Bowen Li
AU - Agostino Pierro
AU - Ana C. Andreazza
AU - Claudia C. dos Santos
AU - Milica Radisic
AB - 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 κB signaling axis.
BT - Science Advances
DA - 2024-03-27
DO - 10.1126/sciadv.adk0164
IS - 13
N2 - 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 κB signaling axis.
PY - 2024
EP - eadk0164
T2 - Science Advances
TI - Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes
UR - https://www.science.org/doi/10.1126/sciadv.adk0164
VL - 10
Y2 - 2024-04-09
ER -