Electrical Stimulation Promotes Cardiac Differentiation of Human Induced Pluripotent Stem Cells

Abstract

Background. Human induced pluripotent stem cells (iPSCs) are an attractive source of cardiomyocytes for cardiac repair and regeneration. In this study, we aim to determine whether acute electrical stimulation of human iPSCs can promote their differentiation to cardiomyocytes. Methods. Human iPSCs were differentiated to cardiac cells by forming embryoid bodies (EBs) for 5 days. EBs were then subjected to brief electrical stimulation and plated down for 14 days. Results. In iPS(Foreskin)-2 cell line, brief electrical stimulation at 65 mV/mm or 200 mV/mm for 5 min significantly increased the percentage of beating EBs present by day 14 after plating. Acute electrical stimulation also significantly increased the cardiac gene expression of ACTC1, TNNT2, MYH7, and MYL7. However, the cardiogenic effect of electrical stimulation was not reproducible in another iPS cell line, CERA007c6. Beating EBs from control and electrically stimulated groups expressed various cardiac-specific transcription factors and contractile muscle markers. Beating EBs were also shown to cycle calcium and were responsive to the chronotropic agents, isoproterenol and carbamylcholine, in a concentration-dependent manner. Conclusions. Our results demonstrate that brief electrical stimulation can promote cardiac differentiation of human iPS cells. The cardiogenic effect of brief electrical stimulation is dependent on the cell line used.

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

“…pacing at the rates below the intrinsic rate is not effective). To account for the dependence of action potential on the beating rate in iPSC-CMS an empirical formula, Bazet (Hernandez et al , 2016; Kim et al , 2010) or Fridericia (Lewis et al , 2015; Maddah et al , 2015) is usually used, that may not accurately correct for the rate dependence in the wide range of beating rates observed after drug treatments. The need for the forced rate correction would be overcome in a more mature and pure ventricular iPSC-CMs that did not demonstrate spontaneous depolarizations.…”

Rapid Electrical Stimulation Increased Cardiac Apoptosis Through Disturbance of Calcium Homeostasis and Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Previously, it was suggested that electrical stimulation promotes cardiac differentiation and maturation of hiPSC-derived cardiomyocytes [40][41][42]. Ruan et al [41] reported that electrical stimulation promotes force maturation of induced pluripotent stem cell-derived cardiac tissue; however, the cardiomyocytes used in this study were only 2 or 3 weeks old.…”

“…Ruan et al [41] reported that electrical stimulation promotes force maturation of induced pluripotent stem cell-derived cardiac tissue; however, the cardiomyocytes used in this study were only 2 or 3 weeks old. Damián Hernández et al [42] reported that electrical stimulation promoted cardiac differentiation; however, the parameters of electrical stimulation were set at 1 Hz and for a very short period of approximately 15 min. The effects of stimulation when extended to a longer time or on older cardiomyocytes remain unknown.…”

An aged human heart tissue model showing age-related molecular and functional deterioration resembling the native heart

“…While hiPSC-derived cardiomyocytes hold promise for human-origin and patient specific disease modeling, it has been widely reported that these cells resemble the fetal cardiomyocytes rather than adult ones 33 . It has been shown in other studies that iCMs mature with time 66 and with mechanical 33,67 or electrical 33,67,68 stimuli. Here we show that regardless of the iPSC origin, iCMs mature in vitro with prolonged culture time, and start showing marks of cellular aging at the later culture stages, through 120 days of culture we conducted in this study.…”