Univ. Prof. Dr. Steffen Hering

Two and three-dimensional models of human pluripotent stem cell derived cardiomyocytes for drug discovery

Human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) serve as in vitro models of human cardiovascular diseases, drug development and for drug safety testing (Saxena et al. 2017, Blinova et al. 2018). Major advantages of hPSC cardiac derivatives over animal models include their human origin, the virtually unlimited supply of cells from different human genetic backgrounds, and the potential to reduce the number of laboratory animals and testing. In order to reach their full potential for routine applications in drug development hPSC-CMs need, however, further refinement. In particular, commonly used irregularly growing monolayer cultures represent native cardiac tissues only rudimentary and recordings of membrane potentials with (commonly used) extracellular electrodes do not provide absolute values of resting and action potentials. Furthermore, contractions of mature (tissue-like) myocardial preparations may lead to movement artefacts and cell detachment during long term culturing.

This project aims to overcome these limitations by developing two and three dimensional hPSC-CMs cultures such as fiber-like structures and spheroids making use of nanostructured surfaces. The project will be carried out in close collaboration with stem cell biologists at IMBA. Maturation and differentiation of the cell models will be analyzed with state-of-the-art electrophysiological methods. We will focus on characterization of the principle inward currents through Nav and Cav and potassium outward currents (e.g. through HERG [Kv11.1] channels). Novel hPSC-CMs models combined with advanced cell array technology are expected to increase the efficiency of drug development and safety pharmacology.

Saxena P, Hortigon-Vinagre MP, Beyl S, Baburin I, Andranovits S, Iqbal SM, Costa A, IJzerman AP, Kügler P, Timin E, Smith GL, Hering S. Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation. Br J Pharmacol. 2017 Sep;174(18):3081-3093.

Blinova K, Dang Q, Millard D, Smith G, Pierson J, Guo L, Brock M, Lu HR, Kraushaar U, Zeng H, Shi H, Zhang X, Sawada K, Osada T, Kanda Y, Sekino Y, Pang L, Feaster TK, Kettenhofen R, Stockbridge N, Strauss DG, Gintant G. International Multisite Study of Human-induced Pluripotent Stem Cell-Derived cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Rep. 2018 Sep 25;24(13):3582-3592.