Cardiomyocytes - "Positive inotropic effects in human iPSC-derived cardiomyocytes can be triggered through a flexible pro-maturation environment"
FLEXcyte 96 application note (0.3 MB) kindly provided by InnoVitro GmbH
High throughput Screening (HTS) scalable techniques with highly predictive cell models are needed to improve the expensive and time-consuming drug development process. Potentially dangerous consequences of side effects on the human heart make safety testing of heart related issues the main focus of pre-clinical drug development studies. However, one of the most commonly used gold standard technique for cardiac contractility measurements, the ex vivo Langendorff set-up, does not efficiently support modern drug development processes as it uses non-predictive animal models on a very low throughput level.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combine a number of features fostering the drug development process such as high predictivity, large scale applicability with high throughput potential, low ethical concerns and cost effectiveness. Yet, when cultured on overly stiff substrates like glass or plastic, the cells are placed under unnecessary stress due to the missing auxotonic physiological environment provided by a flexible substrate.
These unphysiological conditions lead to drastic transcriptional and metabolic deregulation in cardiomyocytes which affect the predictive value of this established cell model. To bridge the gap of predictive contractility measurements and HTS analysis for drug development studies, innoVitro co-developed the FLEXcyte 96 with Nanion Technologies as an add-on for the CardioExcyte 96 platform. With less than 10 μm in thickness and sophisticated surface modification, the polydimethylsiloxane (PDMS) membranes of the FLEXcyte 96 disposable plates offer physiological elasticity of native human heart tissue. As a result hiPSC-derived CM behave in an in vivo manner and finally reach their full potential as a CiPA confirmed model for drug development processes.
Beta-adrenergic agonist isoproterenol and L-type calcium channel agonist S-Bay K8644 are both well known for their positive inotropic effects on the human heart, although common iPSC-CM in vitro assays fail to display this physiological response by showing negative inotropic effects instead.
Here, we show that the auxotonic environment of the FLEXcyte 96 enables mature physiological responses of hiPSC-CMs on positive inotropic substances such as L-type calcium channel agonist S-Bay K8644, beta-adrenergic agonist isoproterenol and cardiac myosin activator omecamtiv mecarbil.