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.
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.
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
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.
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.
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.
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.
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.
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.