Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available from the corresponding authors on reasonable request. RNA-seq data are available from the NCBI GEO, under the accession numbers GSE113871 and GSE115031.
Custom LabVIEW codes for controlling the custom-built 2PLSM are available from the corresponding author on reasonable request.
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We thank W. da Silveira for insights into microarray, RNA-seq and GSEA analysis and the staff of the laboratory of M. Morad for help with GCaMP6 labelling. The work was supported by the National Institutes of Health (R01 HL133308, 8P20 GM103444, U54 GM104941), National Institute of General Medical Sciences (P20GM-103499), start-up funds from Clemson University, the National Science Foundation (NSF; EPS-0903795, 1539034), the NIH Cardiovascular Training Grant (T32 HL007260), SCTR Institute CTSA NIH/NCATS (UL1TR001450) and US Department of Veterans Affairs Merit Review (I01 BX002327); and NIH grants (R03 DE018741 and R01 DE021134 to H.Y). G.H. acknowledges support from NIH/NIDA (1U01DA045300-01A1). This study used the services of the Morphology, Imaging and Instrumentation Core, which is supported by NIH-NIGMS P30 GM103342 to the South Carolina COBRE for Developmentally Based Cardiovascular Diseases and was supported in part by the Genomics Shared Resource, Hollings Cancer Center, and the Medical University of South Carolina (P30 CA138313). The Bioenergetics Profiling Core is supported by the COBRE in Redox, Oxidant Balance and Stress Signalling (NIH/NIGMS P20 GM103542). We dedicate this work to C.C.B.
The authors declare no competing interests.
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Supplementary figures and legends for Supplementary Videos 1–10 and Supplementary Tables 1–7.
GO terms and P values for the overlapping regions of the Venn diagrams of DE genes in mice, pigs, humans and human cardiac organoids with ischaemic cardiac injury.
Top 35 GO terms.
Metabolic-pathway gene sets.
Fibrosis-related gene sets.
Significant P values in the radial-density plots of Figs. 4f, 6b and 7c.
Calcium-handling-related gene sets.
P values from the two-way ANOVA with post hoc Tukey tests in Fig. 7e.
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the organoid for control organoids at day 10.
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the organoid for infarct organoids at day 10.
Bright-field observations of synchronized control organoids at day 10.
Bright-field observations of unsynchronized infarct organoids at day 10.
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the spheroid for infarct CM spheroids at day 10.
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the organoid for control organoids at day 10 (derived from cells for donor B).
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the organoid for infarct organoids at day 10 (derived from cells for donor B).
Bright-field observations of synchronized control organoids at day 10 (derived from cells for donor B).
Bright-field observations of unsynchronized infarct organoids at day 10 (derived from cells for donor B).
Customized two-photon scanned light-sheet microscopy of more than 50 μm below the surface of the organoid for infarct organoids at day 10 (with treatment with an anti-fibrotic drug candidate).
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Richards, D.J., Li, Y., Kerr, C.M. et al. Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nat Biomed Eng 4, 446–462 (2020). https://doi.org/10.1038/s41551-020-0539-4
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