The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Abstract

The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease-and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology. LINKED ARTICLESThis article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials

“…Cardiomyocytes differentiated from iPSCs show concentration-dependent responses to cardioactive drugs, including beating frequency and contractility, which are consistent with clinical effects. 17 Additionally, these cells express S1P 1 and S1P 3 receptors (results not shown). Compound 1-P showed a concentration-dependent decrease in cardiomyocyte beating rate, with a no-effect concentration of 0.1 nM.…”

Allosteric Modulation of K v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

“…To overcome these shortcomings, human-induced pluripotent stem cell-derived cardiomyocytes are now often used for cardiotoxicological screenings. 22 However, thus far, human-induced pluripotent stem cell-derived cardiomyocytes cannot produce dense monolayers of phenotypically homogeneous ventricular cardiomyocytes for high-resolution optical mapping. 23 We hence used NRVM monolayers to study the effects of LUF7244 on the proarrhythmic potential of 3 inadvertent K v 11.1 blockers by optical voltage mapping.…”

Evaluation of the effects of power-frequency magnetic fields on the electrical activity of cardiomyocytes differentiated from human induced pluripotent stem cells

“…These cause differences in each species' tolerance to chemical agents (Price et al, 2008), and might yield false-positive or -negative results when human toxicity is evaluated using experimental animals and cells. Tests using many kinds of known cardioactive compounds have shown that hiPS-CMs are useful for evaluation of pharmacological responsiveness in humans (Sirenko et al, 2013;Khan et al, 2013). Thus, assay systems using hiPS-CMs are likely to provide accurate and efficient screening of candidate drugs.…”

“…CMs derived from hiPS cells (hiPS-CMs) are artificially generated source of human tissue, and their potential for use in medical and pharmacological applications has been intensively examined (Funakoshi et al, 2016;Kawamura et al, 2012;Khan et al, 2013;Sirenko et al, 2013). In the pharmacological field, hiPS-CMs have been confirmed to show appropriate responsiveness to known cardioactive compounds (Sirenko et al, 2013), and hiPS-CMs are expected to contribute to efficient screening of candidate drugs (Khan et al, 2013). HiPS-CMs are becoming a powerful tool to evaluate human responses.…”