Project description
An in vitro cell model for cardiac arrhythmias
Human induced pluripotent stem cells (iPSCs) have recently emerged as good in vitro models for studying tissue pathophysiology. Scientists of the EU-funded SiGNATURE project will employ iPSCs to develop cardiomyocytes and study cardiac arrhythmias, a group of conditions that are increasing in prevalence among European citizens. Using a unique 3D culture system, researchers will mature iPSC-derived cardiomyocytes and investigate them at the genetic and functional level. The work will focus on two gene-associated heart diseases. The iPSC-derived cardiomyocytes will advance modelling of cell-autonomous cardiac diseases and pave the way for personalised in vitro drug screening strategies.
Objective
The incidence of cardiac arrhythmias in Europe is increasing because of aging and unexpected side effects of drugs, such as chemotherapeutics. To understand mechanisms underlying these conditions requires reliable preferably human models. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are presently good candidates since they share the genome of the individual from whom they are derived and can thus recapitulate genetic, ethnic and gender contributions to the cardiac disease phenotypes. However, their immature state and high inter- and intra-line variability is limiting their value as preclinical models.
In the proposed project, I will address these issues through an interdisciplinary approach combining a unique 3D culture maturation system developed in my host lab with my expertise in electrophysiology. I will characterize gene expression and electrical properties of single cardiomyocytes simultaneously with view to directly correlating genes with function and identify molecular markers associated with the functionally mature cardiac phenotype. Two genetic cardiac diseases (one caused by an imprinted gene, the other by a postnatally expressed splice variant) for which the host already has hiPSC lines, will be used as proof of concept that hiPSC-CM maturation in this system is sufficient (i) to reveal disease phenotypes not evident in conventional culture and (ii) to identify molecular markers suitable for selecting mature hiPSC-CMs for drug testing.
Overall, this project will provide the first functionally-relevant gene signature of (mature) hiPSC-CMs, and thus be an important advance in modelling all cardiomyocyte autonomous cardiac diseases more precisely for (personalized) drug screening. The outcome will be available to academic and private researchers to enhance rates of drug discovery and safety, and promote hiPSC-CMs as validated adult cardiac models to replace, at least in part, the use of animal models.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
2333 ZA Leiden
Netherlands