Human Embryonic and Induced Pluripotent Stem Cell–Derived Cardiomyocytes Exhibit Beat Rate Variability and Power-Law Behavior

Abstract

Background-The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. Methods and Results-We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. Conclusions-This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patient's own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers. (Circulation. 2012;125:883-893.)

Biological Pacemakers – A Review

“…This technique has been extended to human cells [36,37]. Mandel et al used the patient's own hair to generate cardiomyocytes from iPSC and showed that these cells were spontaneously active with intrinsic heart rate variability and ability to respond to isoprenaline and carbamylcholine [38].…”

Estado actual de la terapia con células madre en el tratamiento de las cardiopatías: An update

“…En términos amplios, podemos clasificar las células madre según su potencialidad en células madre pluripotenciales (embrionarias o inducidas) y multipotenciales (adultas). Un creciente volumen de evidencia preclínica, avala el gran potencial terapéutico de las células madre pluripotenciales inducidas (iPSC) en patología cardiovascular [9][10][11] . Existen sin embargo, dudas razonables respecto a su eventual efecto tumorigénico y/o inmunogénico, lo que ha dificultado por ahora su traslado a la clínica 12,13 .…”

Stem Cell–Derived Nodal-Like Cardiomyocytes as a Novel Pharmacologic Tool: Insights from Sinoatrial Node Development and Function

“…Second, such a preparation might provide an ideal source with which to create a "biological pacemaker" to replace current electronic pacemakers in treating rhythm disorders. Proof-of-concept experiments with biologic pacemakers have demonstrated some success with the implantation of fetal (Ruhparwar et al, 2002) or adult ) SAN cells and beating embryoid bodies (EBs) derived from embryonic stem cells (ESCs) Xue et al, 2005); cardiomyocytes from induced pluripotent stem cells (iPSCs) also have been produced and characterized (Novak et al, 2010;Mandel et al, 2012) but not yet implanted to form a biologic pacemaker. In addition, adult mesenchymal stem cells, not driven down a cardiac lineage but genetically modified to generate a pacemaker current (I f ), have also proven successful (Potapova et al, 2004;Rosen et al, 2008).…”