Dataset Information

Cardiac organoid model of human myocardial infarction

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113871 | GEO | 2020/04/14

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Ischemia, fibrosis, and remodeling lead to heart failure after severe myocardial infarction (MI). Myoblast sheet transplantation is a promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in this detrimental disease. We hypothesized that in a rat model of MI-induced chronic heart failure this therapy could further be improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression using microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for four weeks. Thereafter, we administered L6-WT (n=15) or L6-HGF (n=16) myoblast sheet therapy. Control rats (n=13) underwent LAD ligation and rethoracotomy without therapy and five rats underwent sham-operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy administration. We analyzed cardiac angiogenesis and left ventricular architecture from histological sections 4 weeks after therapy. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF-expression. Analysis of the L6 rat skeletal myoblast cell line and myoblast cell sheets with constitutive human HGF expression.

Dataset Information

Cardiac organoid model of human myocardial infarction

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure