Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity.
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ABSTRACT:
SUBMITTER: Richards DJ
PROVIDER: S-EPMC7422941 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism.Determining the mechanism of sorafenib-mediated cardiotoxicity.Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2'-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated.Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.
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Project description:While human organoid systems have provided a powerful platform in modeling diseases caused by genetic disorders, non-genetic factors, such as lifestyle and environment, are the largest attributable factors to devastating diseases like cardiovascular disease (CVD), the leading cause of death worldwide. Specifically, myocardial infarction (MI) (i.e., heart attack) makes up ~8.5% of CVD and is a common cause of heart failure with a 40% five-year mortality after the first MI. This highlights an urgent need to develop relevant human heart failure models for drug development. This is further evidenced by the disappointing performance of heart failure drugs in clinical trials during the last decade, which has been partially attributed to the distinct differences between human patient hearts and animal heart failure models. Here, we combined major non-genetic causal factors of MI with our previously established cardiac organoids to create the first human organoid model of cardiac infarction. In particular, we leveraged the diffusion limitation in 3D microtissues to recreate the nutrient diffusion gradient across infarcted hearts (i.e., infarct-border-remote zones) in human cardiac organoids to induce cardiac organotypic response to infarction. This enabled the recapitulation of major MI hallmarks in human cardiac organoids at the transcriptomic, structural and functional level.
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Project description:While human organoid systems have provided a powerful platform in modeling diseases caused by genetic disorders, non-genetic factors, such as lifestyle and environment, are the largest attributable factors to devastating diseases like cardiovascular disease (CVD), the leading cause of death worldwide. Specifically, myocardial infarction (MI) (i.e., heart attack) makes up ~8.5% of CVD and is a common cause of heart failure with a 40% five-year mortality after the first MI. This highlights an urgent need to develop relevant human heart failure models for drug development. This is further evidenced by the disappointing performance of heart failure drugs in clinical trials during the last decade, which has been partially attributed to the distinct differences between human patient hearts and animal heart failure models. Here, we combined major non-genetic causal factors of MI with our previously established cardiac organoids to create the first human organoid model of cardiac infarction. In particular, we leveraged the diffusion limitation in 3D microtissues to recreate the nutrient diffusion gradient across infarcted hearts (i.e., infarct-border-remote zones) in human cardiac organoids to induce cardiac organotypic response to infarction. This enabled the recapitulation of major MI hallmarks in human cardiac organoids at the transcriptomic, structural and functional level.
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