Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias

Wang, Jiaxian; Chen, Aaron; Lieu, Deborah K.; Karakikes, Ioannis; Chen, Gaopeng; Keung, Wendy; Chan, Chun Man; Hajjar, Roger J.; Costa, Kevin D.; Khine, Michelle; Tse, Gary

doi:10.1016/j.biomaterials.2013.07.039

Cited by 63 publications

(61 citation statements)

References 36 publications

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“…Our hESC-VCMs express reduced levels of important channels and Ca 2+ handling genes eg KCNJ2 and PLN etc, consistent with previous publications [8,17,50]. On a multicellular level, the random arrangement of CX43 and low conduction velocity reported here are also in line with our recent paper showing that the conduction pattern of hESC-VCMs cultured on 2-dimensional surfaces are immature and isotropic [51]. Successful drug testing requires that hESC- V CMs exhibit electrophysiological and survival properties similar to adult CMs in vivo.…”

Section: Discussionsupporting

confidence: 93%

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Transcriptome-Guided Functional Analyses Reveal Novel Biological Properties and Regulatory Hierarchy of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes Crucial for Maturation

et al. 2013

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Human (h) embryonic stem cells (ESC) represent an unlimited source of cardiomyocytes (CMs); however, these differentiated cells are immature. Thus far, gene profiling studies have been performed with non-purified or non-chamber specific CMs. Here we took a combinatorial approach of using systems biology to guide functional discoveries of novel biological properties of purified hESC-derived ventricular (V) CMs. We profiled the transcriptomes of hESCs, hESC-, fetal (hF) and adult (hA) VCMs, and showed that hESC-VCMs displayed a unique transcriptomic signature. Not only did a detailed comparison between hESC-VCMs and hF-VCMs confirm known expression changes in metabolic and contractile genes, it further revealed novel differences in genes associated with reactive oxygen species (ROS) metabolism, migration and cell cycle, as well as potassium and calcium ion transport. Following these guides, we functionally confirmed that hESC-VCMs expressed IKATP with immature properties, and were accordingly vulnerable to hypoxia/reoxygenation-induced apoptosis. For mechanistic insights, our coexpression and promoter analyses uncovered a novel transcriptional hierarchy involving select transcription factors (GATA4, HAND1, NKX2.5, PPARGC1A and TCF8), and genes involved in contraction, calcium homeostasis and metabolism. These data highlight novel expression and functional differences between hESC-VCMs and their fetal counterparts, and offer insights into the underlying cell developmental state. These findings may lead to mechanism-based methods for in vitro driven maturation.

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Section: Discussionsupporting

confidence: 93%

“…Furthermore, CX43-positive gap junctions are aligned at the intercalated disc of adult CMs [26] but such was not the case for hESC- V CMs, whose CX43-positive gap junctions were randomly distributed (Figure 1H). Evidently, conduction pattern was isotropic as opposed to anisotropic as observed in the native myocardium [27]. …”

Section: Resultsmentioning

confidence: 99%

Transcriptome-Guided Functional Analyses Reveal Novel Biological Properties and Regulatory Hierarchy of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes Crucial for Maturation

et al. 2013

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“…While several factors such as biochemical and mechanical cues affect cells, topographical cues have been found to play a pivotal role in directing the function and behavior of cells. Cells are exposed to multiscale topographical environments of the ECM, for which the dimensions span micrometers to nanometers [4][5][6][7][8][9][10][11][12][13]. Therefore, a clinically reliable artificial ECM that can be used for tissue transplantation must possess multiscale structures that can provide cells with topographical cues similar to that of a natural ECM.…”

Section: Introductionmentioning

confidence: 98%

Multiscale engineered hierarchical structures with precisely controlled sizes for bio-inspired cell culture

2015

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“…15,16 Furthermore, different types of topographies, such as aligned grooves and pillars, have been used to regulate cell morphology and the development of anisotropic conduction patterns. 17–19 In the case of cardiac muscle, it has been shown that an underlying nanoscale topography which mimics the dimensions and orientation of the cardiac extracellular matrix (ECM) is capable of promoting the anisotropic orientation of cultured rodent cardiomyocytes. 15 The use of biomimetic topographies capable of orienting cells in this manner helps drive the development of cellular structure and function in engineered cardiac tissues.…”

Section: Introductionmentioning

confidence: 99%

Nanotopography-Induced Structural Anisotropy and Sarcomere Development in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Carson¹,

Hnilova²,

Yang³

et al. 2016

ACS Appl. Mater. Interfaces

162

182

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Understanding the phenotypic development of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a prerequisite to advancing regenerative cardiac therapy, disease modeling, and drug screening applications. Lack of consistent hiPSC-CM in vitro data can be largely attributed to the inability of conventional culture methods to mimic the structural, biochemical, and mechanical aspects of the myocardial niche accurately. Here, we present a nanogrid culture array comprised of nanogrooved topographies, with groove widths ranging from 350 to 2000 nm, to study the effect of different nanoscale structures on the structural development of hiPSC-CMs in vitro. Nanotopographies were designed to have a biomimetic interface, based on observations of the oriented myocardial extracellular matrix (ECM) fibers found in vivo. Nanotopographic substrates were integrated with a self-assembling chimeric peptide containing the Arg-Gly-Asp (RGD) cell adhesion motif. Using this platform, cell adhesion to peptide-coated substrates was found to be comparable to that of conventional fibronectin-coated surfaces. Cardiomyocyte organization and structural development were found to be dependent on the nanotopographical feature size in a biphasic manner, with improved development achieved on grooves in the 700–1000 nm range. These findings highlight the capability of surface-functionalized, bioinspired substrates to influence cardiomyocyte development, and the capacity for such platforms to serve as a versatile assay for investigating the role of topographical guidance cues on cell behavior. Such substrates could potentially create more physiologically relevant in vitro cardiac tissues for future drug screening and disease modeling studies.

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Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias

Cited by 63 publications

References 36 publications

Transcriptome-Guided Functional Analyses Reveal Novel Biological Properties and Regulatory Hierarchy of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes Crucial for Maturation

Transcriptome-Guided Functional Analyses Reveal Novel Biological Properties and Regulatory Hierarchy of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes Crucial for Maturation

Multiscale engineered hierarchical structures with precisely controlled sizes for bio-inspired cell culture

Nanotopography-Induced Structural Anisotropy and Sarcomere Development in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells

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