HEART
Cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) hold great potential as human in vitro models for studying heart disease and for drug safety screening. Nevertheless, their associated immaturity relative to the adult myocardium limits their utility in cardiac research. Over the last decades, 3D in vitro models from hPSC-CMs have become a promising and highly advanced model for studying cardiac disease since they exhibit a higher degree of maturation based on various features, including a more
defined cellular organization (e.g., sarcomeric assembly and mitochondrial maturation), an expression pattern of maturation-related genes, and an enhanced contractile function, when compared to two-dimensional cell culture. The Heart team is working towards more physiological novel human cell-based in vitro models of the human heart using hPSC-CMs.
Multi-Heart Plate
Although advanced in-vitro cardiac models like organoids, heart-on-chips, and engineered heart tissues offer significant benefits, they fall short in replicating the heart’s fluid-pumping function. Engineered cardiac chambers address this gap. In this project, we build on insights from the bioreactor mini-heart platform, advancing toward the next generation of cardiac chambers. To create a more adaptable and standardized model, we developed the Multi-heart plate—a modular, versatile system that uses 40% fewer cells per chamber and is compatible with a 12-well plate format. After successful characterization, this platform will be used in disease model applications.
Funding
ERC Advanced – Heart2Beat
Researchers
PhD Candidate
PhD Candidate
Postdoc
Postdoc
Full Professor
Mini heart
Engineered pumping cardiac chambers are a promising technology to study the effects of hemodynamic loads in cardiac performance, in healthy and diseased conditions.
Using a sacrificial moulding approach, we developed a miniature human cardiac chamber that recapitulates the pumping function of the heart.
In this project, we aim to perform a functional and biomechanical characterization of the pumping chambers under static and dynamic load conditioning. This will provide the basis for accurate disease models using clinically-relevant pressure-volume readouts.
Researchers
Postdoc
Marcelo C. Ribeiro
Guest Researcher
Full Professor
Micro-Engineered Heart Tissues on a chip
We work towards a continuous improvement of 3D micro-engineered heart tissues (uEHTs) to recapitulate their physiological complexity by introducing multiple relevant cell types in a controlled ratio. Particularly, we focus on the crosstalk between cardiomyocytes and endothelial cells, since in vivo these cell types are in direct contact and endothelial cells play a major role in the regulation of cardiomyocyte’s structural organization, energy metabolism and contractile performance. The establishment of this model in a heart-on-chip system will provide better understanding of the role of the endothelial cells in the (patho-)physiology of human cardiomyocytes.
Arryhthmia on a chip
For studying disturbances in electrical conduction in cardiac tissue, it is necessary to develop a human cardiomyocyte-based model that can recapitulate in vivo action potential wavefront propagation. For this, we generate a geometrically confined 3D cardiac tissue prone to arrhythmic activation patterns. In parallel, we develop custom made methods for local electrical pacing, and generate a ChannelRhodopsin-expressing cell line for blue light pacing of a “pacemaker node” in the tissue. This, together with the custom built imaging setup and data interpretation, enables us to quantify the pro-arrhythmic properties of genetic mutations, drugs, or toxins.
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.
Researchers
Postdoc
Marcelo C. Ribeiro
Guest Researcher
Full Professor
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
Guest 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
Heart-Brain Axis on a chip
The heart-brain axis is crucial for maintaining homeostasis in the body, including regulation of the heartbeat. In our lab, we work on developing a chip system that envelops the entire axis, from brain, through nerve, to heart. In this model, we want to include both a sympathetic and a parasympathetic component. The model can then be chemically or electrically manipulated in order to model pathologies of the heart-brain axis on chip.
Funding
NOCI
Researchers
PhD Candidate
Assistant Professor
Full Professor
Full Professor
Advanced 3D Cardiac Tissue Models for High-Throughput Screening and Translational Research
Three-dimensional cardiac tissues with controlled spatial organization, enabling the integration of different cell populations within defined tissue architectures. Such constructs have the potential to promote enhanced tissue maturation and physiological relevance while supporting the study of cardiac development, disease mechanisms, and tissue remodeling. By improving the reproducibility and scalability of 3D cardiac tissue technologies, they can facilitate drug testing, disease modeling, and high-throughput screening for biomedical research and pharmaceutical applications.
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
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.