Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype

American Journal of Physiology - Heart and Circulatory Physiology - Tập 305 Số 6 - Trang H913-H922 - 2013
Christine Y. Ivashchenko1, G. C. Teg Pipes1, Irina Lozinskaya1, Zuojun Lin1, Xiaoping Xu1, Saul Needle1, Eugene T. Grygielko1, Erding Hu1, John R. Toomey1, John J. Lepore1, Robert N. Willette1
1Heart Failure Discovery Performance Unit, Metabolic and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania

Tóm tắt

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been recently derived and are used for basic research, cardiotoxicity assessment, and phenotypic screening. However, the hiPS-CM phenotype is dependent on their derivation, age, and culture conditions, and there is disagreement as to what constitutes a functional hiPS-CM. The aim of the present study is to characterize the temporal changes in hiPS-CM phenotype by examining five determinants of cardiomyocyte function: gene expression, ion channel functionality, calcium cycling, metabolic activity, and responsiveness to cardioactive compounds. Based on both gene expression and electrophysiological properties, at day 30 of differentiation, hiPS-CMs are immature cells that, with time in culture, progressively develop a more mature phenotype without signs of dedifferentiation. This phenotype is characterized by adult-like gene expression patterns, action potentials exhibiting ventricular atrial and nodal properties, coordinated calcium cycling and beating, suggesting the formation of a functional syncytium. Pharmacological responses to pathological (endothelin-1), physiological (IGF-1), and autonomic (isoproterenol) stimuli similar to those characteristic of isolated adult cardiac myocytes are present in maturing hiPS-CMs. In addition, thyroid hormone treatment of hiPS-CMs attenuated the fetal gene expression in favor of a more adult-like pattern. Overall, hiPS-CMs progressively acquire functionality when maintained in culture for a prolonged period of time. The description of this evolving phenotype helps to identify optimal use of hiPS-CMs for a range of research applications.

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American Journal of Physiology - Heart and Circulatory Physiology

Tập 305 Số 6

H913-H922

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