PSC-derived cardiomyocytes in drug screening: A story of maturation

Cardiomyocytes derived from human pluripotent stem cells (PSC-CMs) are a promising tool for studying drug effects in pre-clinical cardiotoxicity and pro-arrhythmia screenings. However, with current differentiation protocols the generated cells display an immature, fetal-like phenotype in regard to cell structure and electrophysiological properties. This raises the question if drug response data generated with immature cells are representative of mature cardiomyocytes.

In a recent publication, Monteiro da Rocha et al. (2017) introduce a novel platform for the direct comparison of fetal-like and mature cardiomyocytes in drug screening. The assay uses human pluripotent stem cells (PSCs) that are either differentiated into fetal-like cardiomyocytes or further matured into adult cardiomyocytes using a previously described extracellular matrix (Herron et al.2016). To exclude unwanted side effects through contaminating cells, the differentiated cells were purified using the PSC-Derived Cardiomyocyte Kit, human. With this method, purities of up to 98% were routinely achieved, thus eliminating the need for time-consuming genetic or metabolic selection methods like lactate starvation that might cause unwanted physiological changes. Cell purity was fully comparable to commercially available PSC-CMs.

The authors observed a clear correlation between maturation state and drug response. More specifically, they could show that fetal-like CMs exhibit higher sensitivity to the tested compounds than mature PSC-CMs. Therefore, the maturation state of PSC-CMs is a critical parameter for pre-clinical pro-arrhythmia and cardiotoxicity screens. The authors conclude that their novel platform enables drug screening on both, fetal-like and mature cardiomyocytes, allowing a comprehensive examination of drug effects during cardiac development.

In summary, Monteiro da Rocha et al. show that
  • The maturation state of PSC-CMs has an impact on drug responsiveness
  • The maturation state of PSC-CMs should be a criterion in pro-arrhythmia and cardiotoxicity screens
  • PSC-CM purification using the MACS® Technology provides highly pure, functional cardiomyocytes that are in all aspects comparable to commercial cell sources

References:

Extracellular Matrix-Mediated Maturation of Human Pluripotent Stem Cell-Derived Cardiac Monolayer Structure and Electrophysiological Function.
Herron TJ, Rocha AM, Campbell KF, Ponce-Balbuena D, Willis BC, Guerrero-Serna G, Liu Q, Klos M, Musa H, Zarzoso M, Bizy A, Furness J, Anumonwo J, Mironov S, Jalife J.
Circ Arrhythm Electrophysiol. 2016 Apr;9(4):e003638. doi: 10.1161/CIRCEP.113.003638.

hiPSC-CM Monolayer Maturation State Determines Drug Responsiveness in High Throughput Pro-Arrhythmia Screen.
da Rocha AM, Campbell K, Mironov S, Jiang J, Mundada L, Guerrero-Serna G, Jalife J, Herron TJ.
Sci Rep. 2017 Oct 23;7(1):13834. doi: 10.1038/s41598-017-13590-y.


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Products used in the publication:

PSC-Derived Cardiomyocyte Isolation Kit, human

StemMACS™ iPS-Brew XF, human


Additional products supporting research on PSC-derived cardiomyocytes:

Anti-α-Actinin (Sarcomeric) antibodies

Anti-Cardiac-Troponin T antibodies

Anti-MLC2a antibodies

Anti-MLC2v antibodies

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