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Electrophysiological and Contractile Function of Cardiomyocytes Derived from Human Embryonic Stem Cells

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Electrophysiological and Contractile Function of Cardiomyocytes Derived from Human Embryonic Stem Cells Progress in Biophysics and Molecular Biology 110 (2012) 178e195 Contents lists available at SciVerse ScienceDirect Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio Review Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells Adriana Blazeski a, Renjun Zhu a, David W. Hunter a, Seth H. Weinberg a, Kenneth R. Boheler c, Elias T. Zambidis b, Leslie Tung a,* a Department of Biomedical Engineering, The Johns Hopkins University, 720 Rutland Ave., Baltimore, MD 21205, USA b Institute for Cell Engineering and Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD, USA c Molecular Cardiology and Stem Cell Unit, National Institute on Aging, Baltimore, MD, USA article info abstract Article history: Human embryonic stem cells have emerged as the prototypical source from which cardiomyocytes can Available online 7 August 2012 be derived for use in drug discovery and cell therapy. However, such applications require that these cardiomyocytes (hESC-CMs) faithfully recapitulate the physiology of adult cells, especially in relation to Keywords: their electrophysiological and contractile function. We review what is known about the electrophysi- Human embryonic stem cell ology of hESC-CMs in terms of beating rate, action potential characteristics, ionic currents, and cellular Cardiac cell coupling as well as their contractility in terms of calcium cycling and contraction. We also discuss the Embryoid body heterogeneity in cellular phenotypes that arises from variability in cardiac differentiation, maturation, Electrophysiology Contraction and culture conditions, and summarize present strategies that have been implemented to reduce this Optical mapping heterogeneity. Finally, we present original electrophysiological data from optical maps of hESC-CM clusters. Ó 2012 Elsevier Ltd. All rights reserved. Contents 1. Introduction . ........................179 2. Beatingrate ................................................................ ............................... ........................179 2.1. Adrenergic and cholinergic responses . ..........................................180 2.2. Pharmacological responses . ..........................................180 3. Electrophysiology . ........................180 3.1. Action potentials . ..................................................180 3.1.1. Microelectrode and patch clamp recordings . ...........................180 3.1.2. Field potentials . ..........................................181 3.1.3. Optical mapping . ..........................................181 3.2. Ionic currents . ..................................................183 3.3. Cellecell coupling . ..................................................184 3.3.1. Gap junctions . ..........................................184 3.3.2. Conduction . ..........................................184 4. Contractility . ........................185 4.1. Contraction and force generation . ..........................................185 4.2. Calcium cycling . ..................................................185 5. Cellular heterogeneity and maturation . ........................186 5.1. Heterogeneity of differentiated cells . ..........................................186 5.2. Heterogeneity of electrophysiological phenotypes of hESC-CMs . ...........................187 5.3. Transcriptional profiling of hESC-CMs and cellular maturation . ...........................187 5.4. Functional maturation of hESC-CMs . ..........................................188 5.4.1. Native biological environment . ......................................188 * Corresponding author. Tel.: þ1 410 955 9603; fax: þ1 410 502 9814. E-mail address: [email protected] (L. Tung). 0079-6107/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pbiomolbio.2012.07.012 A. Blazeski et al. / Progress in Biophysics and Molecular Biology 110 (2012) 178e195 179 6. Bioengineering the cellular environment . ............................................189 6.1. Three-dimensional culture . .......................189 6.2. Mechanical stimulation and topographic cues . .......................189 6.3. Non-cardiomyocyte influences . .......................190 6.4. Cell culture environment . .......................190 7. Conclusion . .................................................191 Editors’ note................................................................ .......................................................191 Acknowledgments . .......................191 References................................................................. ................................ .......................191 1. Introduction Essential for all of these applications is the proviso that the cells recapitulate native physiological function. Thus, the goal of this Over the past several decades, revolutionary advances in the article is to review the known functional characteristics of hESC- cardiac field have occurred with the advent of human pluripotent CMs. Although previous studies have examined these characteris- stem cells and their differentiation into cardiomyocytes (CMs). tics largely from a genomic perspective, we focus here on contractile Much attention has been directed toward the potential clinical and electrophysiological function. At the elemental level, this means application of these cells in the context of regenerative medicine the contractile structure of the cell (sarcomere and myofilament and cell-based therapy [for reviews, see (Codina et al., 2010; Habib organization) and expression of ion channel and calcium cycling et al., 2008; Laflamme et al., 2007b; Li et al., 2009)]. Despite early proteins. At the integrative level is cellular function, which includes successes with basic science studies and experimentation using contractility, intracellular calcium release and uptake, action animal hearts, clinical studies in general have not yet met with potentials, drug responses, and intercellular coupling. The final level similar success (Lovell and Mathur, 2010). On the other hand, these is physiological function, which has been well characterized in adult cells hold immediate promise as a new generation of experimental cells and tissue in terms of contractility [forceefrequency relation models never before possible. Previously, the availability of human (Endoh, 2004), forceelength relation (Shiels and White, 2008) and tissue for experimentation was limited to tissue biopsies and to intracellular calcium kinetics (Sobie et al., 2006)], electrophysiology hearts that are unsuitable for or made available by organ trans- [restitution (rate-dependence) of action potential duration (Franz, plantation. For the most part, fundamental knowledge regarding 2003), conduction velocity restitution (Weiss et al., 2002)] and the functioning of cardiac tissue under normal or diseased condi- excitationecontraction coupling (Bers, 2008). tions has relied on animal models [for reviews, see (Hamlin, 2007; In the sections that follow, we summarize the reported elec- McCauley and Wehrens, 2009; Milan and MacRae, 2005)]. These trophysiological and contractile properties of hESC-CMs, recog- models approximate the human condition and have been used for nizing that the properties may be rather diverse. Heterogeneity can mechanistic studies at a molecular level. arise from the variability in cardiac differentiation that occurs Today, many types of human pluripotent stem cells are being across cell lines, differentiation protocols, time of differentiation investigated for their potential to produce functional CMs, and maturation of the cells, and culture conditions in different including adult bone marrow-derived cells, bone marrow-derived laboratories. The absence of a well-defined phenotype of the cells is mesenchymal stem cells, adipose-derived cells, embryonic stem an unavoidable limitation at this time and may present a significant cells, endothelial progenitor cells, skeletal myoblasts, resident hurdle to the usage of hESC-CMs. The issues of heterogeneity and cardiac stem cells, and, most recently, induced pluripotent stem maturation and avenues for improvement will be addressed in cells (Li et al., 2009). In this article, we will focus on CMs derived detail in the last section. Finally, we include original electrophysi- from human embryonic stem cells (hESC-CMs), first reported in ological data that we have obtained from optical maps of clusters of 2001 (Kehat et al., 2001). At present, this cell type best produces hESC-CMs. functional CMs and is particularly relevant because it is widely used as the gold standard against which other pluripotent stem cells are 2. Beating rate compared. The potential usages of hESC-CMs are several-fold. First, they Cardiac differentiation in hESCs has been induced by a variety of are expected to be more clinically relevant than animal models techniques (Burridge et al., 2012), but commonly involves culturing for the purposes of toxicity testing and drug discovery and an aggregate of hESCs termed an embryoid body1 (hEB). The first development (Davis et al., 2011; He et al., 2007; Mandenius et al., visual clue of CM differentiation and the presence of hESC-CMs 2011; Zeevi-Levin et al., 2012). The cells can be subjected to within hEBs is the onset of spontaneous synchronized contrac- detailed analysis of their molecular, pharmacological, electro- tion. This automaticity implies pacemaker activity within hEBs physiological
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