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.
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.
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).
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.