Pharmacological response of human cardiomyocytes derived from virus-free induced pluripotent stem cells

Abstract

Virus-free hiPSCs differentiate efficiently into cardiomyocytes with cardiac-specific molecular, structural, and functional properties that recapitulate the developmental ontogeny of cardiogenesis. These results, coupled with the potential to generate patient-specific hiPSC lines, hold great promise for the development of an in vitro platform for drug pharmacogenomics, disease modelling, and regenerative medicine.

Determination of Appropriate Stage of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Drug Screening and Pharmacological Evaluation In Vitro

“…27 Several reports have demonstrated that hiPS-CMs at day 20 to 40 of differentiation have electrophysiological properties and respond to ion channel blockers. [12][13][14] In the present study, electrophysiological responses to ion channel blockers in d30CMs were similar to those in d60CMs and d90CMs, although the sensitivity to the calcium channel blocker was weaker. These functional assays showed that functions related to the β-adrenergic pathway and electrophysiological properties in hiPS-CMs did not change markedly until day 90 of differentiation.…”

Human Pluripotent Stem Cells and Drug Discovery: A New Beginning

“…The FDA has thus recognised QT prolongation as an important variable which needs to be addressed during drug development while the International Conference of Harmonisation (ICH) Expert Working Group (EWG) for drug development has placed risk assessments for delayed ventricular repolarisation as standard procedure of preclinical evaluation of new chemical entities 24 . Cardiomyocytes differentiated from hPSCs open a new paradigm in regenerative medicine 25,26 , disease modelling 20,27 , drug discovery [18][19][20]28 and understanding developmental phenomena 17,29 . Similar to their adult counterparts, hPSC-derived cardiomyocytes express cardiac genes, structural proteins and ion channels 17,30 as well as exhibit a functional excitation-contraction coupling system which could be modulated through β1/β2-adrenergic and muscarinic receptor agonists 31 .…”

“…A number of studies have demonstrated the potential application of hPSCcardiomyocytes in evaluating pharmacological safety 23,[32][33][34][35][36] . For example, while E-4031 (I Kr blocker) and Satalol (class III anti-arrhythmic agent; I Ks blocker) were reported to induce QT prolongation, administration of quinidine (class I anti-arrhythmic agent; I Na blocker) and TTX (Na + channel blocker) resulted in a dose-dependent reduction in conduction velocity 18,32 . With the establishment of hiPSC technology, patientspecific cardiomyocytes could be generated, providing unprecedented insight into the molecular mechanisms surrounding disease pathogenesis 20 .…”

“…Drawback surrounding hPSC-cardiomyocytes is their failure to completely develop a mature phenotype. Irregular sarcomeric organisation 18,31 , multi-angular morphologies (spindle, round, triangular), absence of a T-tubule system 31 and the expression of foetal proteins (e.g. SMA, Cx45) 15,39,40 suggest hPSC-cardiomyocytes are structurally more foetal-like in nature.…”

“…The ability of human pluripotent stem cells (hPSCs) to self-renew and differentiate into virtually any cell type of the three germ layers provides an unparalleled advantage over somatic cell test systems 12,13 . Their unlimited supply and reproducible differentiation [14][15][16][17] into desired cell types allows for unique opportunities in drug development 5, [18][19][20][21] . In this mini-review, we direct our focus on the advantages and disadvantages of utilising hPSC-derived cell types as drug discovery platforms with special emphasis on cardioand hepatotoxicity; forerunners for drug attrition as well as embryotoxicity.…”