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
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.
Researchers
Postdoc
Marcelo C. Ribeiro
Guest Researcher
Full Professor
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.
Funding
Predict2
Researchers
PhD Candidate
Assistant Professor
Full Professor
Lymphatic system with cardiac tissue on a chip
The lymphatic system has an important role in the human body as it controls fluid homeostasis in the body, and it regulates the infiltration of immune cells to infected tissue, indicating its importance in inflammatory resolution. Despite its importance in disease progression and resolution, there are no current organ-on-chip systems that incorporate the lymphatic vasculature. In this model we want to incorporate the lymphatic system with cardiac tissue on chip, to get an improved disease model with control over lymphatic functionality
NWA-ORC 2019 1292.19.019
Researchers
PhD Candidate
Lecturer
Full Professor
Multiplex micro-engineered patient-specific tissues array for artificial intelligence disease prediction
This project will focus on developing a microfluidic array of micro-engineered heart tissues (µEHT) that combine with artificial intelligence (AI) software, aims to predict disease developments in patients. The microfluidic networks will allow users to control the perfusions of each µEHT. Besides, we will assess the effect of cytokines and different drug compounds on patient-specific µEHT. This platform will revolutionize not only research methods in academia, but also for clinical test in hospitals and drug development in industries.
Funding
Digipredict
Researchers
PhD Candidate
Full Professor
Marcelo C. Ribeiro
Guest Researcher
A screening platform for cardiotoxcicity
Cardiotoxicity is one of the main adverse effects of cancer therapy and is a main cause of drug withdrawal. Cardiotoxicity has been extensively assessed in animal models which are not predictive for drug-induced cardiotoxicity in humans. Human pluripotent stem cell (hPSC)-derived cardiomyocytes provide a reliable source of human cardiomyocytes and have already proven valuable for cardiotoxicity studies and may offer a solution to this problem.
We developed a platform of 2D and 3D assays that can predict molecular and functional aspects of cardiotoxicity in hPSC-derived cardiomyocytes.
Researchers
Assistant Professor
Postdoc
Research Technician
Full Professor
Identification of key regulatory elements for cardiac specification and maturation
Identification of the molecular pathways and regulatory elements involved in cardiac subtype specification and maturation is of great importance to be able to understand and modulate the regulatory networks operating in cardiac progenitor cells and their maturation in vitro. HPSC are differentiated towards atrial and ventricular cardiomyocytes which are further matured in EHTs. Transcriptomic and epigenomic analysis by single-cell RNA sequencing and scATAC-seq at specific developmental timepoints will reveal key signaling and transcription factors to be used to further modulate cardiac specification and improve cardiomyocyte maturation. Ultimately, these results will contribute to improving cardiac disease models in vitro and personalized medicine.
Funding
TOP-ZonMw
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
Postdoc
Marcelo C. Ribeiro
Guest Researcher
Full Professor
Drug-induced cardiotoxicity by anti-viral (COVID-19) treatments
The COVID-19 pandemic has demanded for novel drug development. Drug-induced cardiotoxicity is a major side effect of drug treatments due to insufficient and non-representative testing methods. Anti-viral drugs may be effective in inhibiting the virus, but may potentially be damaging to the heart. Hospitalized COVID-19 patients are therefore at risk of getting cardiac damage after infection and receiving these treatments. In this research, we use a 3D EHT platform that can predict the cardiotoxic effects of these drugs in hPSC-derived cardiomyocytes.
Funding
Monaco-Sprint
Researchers
PhD Candidate
Research Technician
Assistant Professor
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
Postdoc
Full Professor
Exercise-on-a-Chip; understanding how exercise might injury the heart
Exercise improves cardiovascular health and reduces risk factors for cardiovascular diseases. Controversially, studies involving vigorous endurance exercise demonstrate an increase in cardiac troponin, a biomarker for cardiac injury. The mechanism of exercise-induced troponin remains to be identified. Current models have major limitations that complicate the identification of this mechanism. In this project, the main goal is to mimic exercise in engineered heart tissue by electrical pacing. This “exercise-on-a-chip” model may help us to unravel the pathological or physiological effects of endurance exercise.
Collaboration with the department of physiology of the Radboud UMC.
Funding
NWO
Researchers
Guest PhD Candidate
Research Technician
Postdoc
Postdoc
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
Adjunct Professor
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
PhD Candidate
Marcelo C. Ribeiro
Guest Researcher
Full Professor