Human Engineered Heart Tissues
Over the last decades, 3D engineered heart tissues (EHTs) from hPSC-CMs have become a promising and highly advanced model for studying cardiac disease, since EHT CMs exhibit a higher degree of maturation when compared to two dimensional CMs. At AST we developed a versatile platform for the generation and functional analysis of 3D EHTs using hPSC-CMs.
Genetic cardiomyopathies in EHTs: disease mechanisms, patient-relevant questions, and new treatments
Bridging the gap between engineering and medicine involves applying our models to model disease and answer real-world patient questions. In this project, we aim for this by applying our engineered heart tissues to model genetic cardiac disease. In fact, several projects are ongoing to model three cardiomyopathies. The first investigates a mutation in lamin A in collaboration with Maastricht UMC. The second focuses on PLN R14del, a Dutch founder mutation with over 1800 mutation carriers identified worldwide. Lastly, we investigate hypertrophic cardiomyopathies in collaboration with Amsterdam UMC. This project dives into the mechanisms underlying hypertrophic cardiomyopathies and explores potential treatments.
Funding
Crazy idea PLN foundation, crazy idea LMNA Cardiac, NWO Open Competition HEARTTWIN
HEARTTWIN: Two models to understand and treat hypertrophic cardiomyopathy
Bridging the gap between engineering and medicine involves applying our models to model disease and answer real-world patient questions. In this project, we aim to do this by applying our engineered heart tissues to model hypertrophic cardiomyopathy. This project dives into the mechanisms underlying the disease and explores potential treatments. HEARTTWIN is a collaboration with the Amsterdam UMC.
Funding
ZonMw Open Competition
Researchers
PhD Candidate
Assistant Professor
Full Professor
Versatile platform that allows mechanical and electrical stimulation to improve maturation of engineering 3D cardiac tissues using hPSCs
Current animal models are not reliable enough to predict responses in humans. Therefore, there is an urgent need to use an advanced human-based models for the assessment of organ function. In vitro 3D cardiac models have shown the potential to mimic in vivo organization, functionality and cell-cell interaction, essential to resemble the human heart to study the pharmacodynamics and pharmacokinetics during preclinical studies of drug development. The physiological performance of cardiomyocytes is crucial to assess the heart function following drug treatment or to evaluate a disease phenotype. In this project, we focus on obtaining an in vitro 3D cardiac tissue that is most representative of the human heart.
Metabolomics and proteomics
Bridge mass spectrometry-based -OMICS technologies (in particular metabolomics and proteomics) and advanced in vitro heart models, such as 3D-EHT and µ3D-EHT, to enable personalized disease modeling and preclinical drug screening in metabolic cardiomyopathies.
This project represents a joint effort between the University of Twente (AST) and the RadboudUMC (TML/Neurology).
Funding
TURBO grant
Researchers
Federica Conte
Postdoc
Research Technician
Full Professor
Genome CRISPR screen to identify targets of cardiac differentiation and disease
Inherited cardiac diseases, such as arrhythmia’s and cardiomyopathy, are caused by single or multiple mutations in cardiac genes. Fundamental knowledge on in vitro differentiation is key to make major advances in disease modeling of inherited diseases. By performing CRISPR genome-wide loss-of-function screens and using our developed 3D-EHT platform, we can identify key factors in cardiac development and inherited cardiac disease.
Funding
ZonMw
Exercise-like stimulation in LMNA EHTs
Previously, our group published the MICRO-ATHLETE study in which EHTs were stimulated as if they were exercising. In this project, we go one step further by exercising diseased EHTs. The goal is to investigate the influence of exercise-like stimulation on disease phenotype. Since cardiolaminopathies (cardiac disease due to LMNA mutations) are a mechanical disease, we test the protocol in LMNA context. The goal is not only to learn more about the disease mechanisms but also to answer patient-relevant questions.