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

TitleEffect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias
Authors
KeywordsAnisotropy
Arrhythmias
Human embryonic stem cells
Reentry
Ventricular cardiomyocytes
Issue Date2013
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/biomaterials
Citation
Biomaterials, 2013, v. 34 n. 35, p. 8878-8886 How to Cite?
AbstractHuman (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC-derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR = LCV/TCV = 1.8-2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17-23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by beta adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias.
Persistent Identifierhttp://hdl.handle.net/10722/189343
ISSN
2015 Impact Factor: 8.387
2015 SCImago Journal Rankings: 3.565
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, Jen_US
dc.contributor.authorChen, Aen_US
dc.contributor.authorLieu, DKen_US
dc.contributor.authorKarakikes, Ien_US
dc.contributor.authorChen, Gen_US
dc.contributor.authorKeung, Wen_US
dc.contributor.authorChan, CWYen_US
dc.contributor.authorHajjar, RJen_US
dc.contributor.authorCosta, KD-
dc.contributor.authorKhine, M-
dc.contributor.authorLi, RA-
dc.date.accessioned2013-09-17T14:36:35Z-
dc.date.available2013-09-17T14:36:35Z-
dc.date.issued2013en_US
dc.identifier.citationBiomaterials, 2013, v. 34 n. 35, p. 8878-8886en_US
dc.identifier.issn0142-9612-
dc.identifier.urihttp://hdl.handle.net/10722/189343-
dc.description.abstractHuman (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC-derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR = LCV/TCV = 1.8-2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17-23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by beta adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias.-
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/biomaterials-
dc.relation.ispartofBiomaterialsen_US
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Biomaterials. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biomaterials, [VOL 34, ISSUE 35, 2013] DOI 10.1016/j.biomaterials.2013.07.039-
dc.subjectAnisotropy-
dc.subjectArrhythmias-
dc.subjectHuman embryonic stem cells-
dc.subjectReentry-
dc.subjectVentricular cardiomyocytes-
dc.titleEffect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmiasen_US
dc.typeArticleen_US
dc.identifier.emailChan, CWY: camchan@hku.hken_US
dc.identifier.emailLi, RA: ronaldli@HKUCC.hku.hk-
dc.identifier.authorityChan, CWY=rp01311en_US
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.biomaterials.2013.07.039-
dc.identifier.pmid23942210-
dc.identifier.scopuseid_2-s2.0-84883234192-
dc.identifier.hkuros222596en_US
dc.identifier.hkuros222853-
dc.identifier.volume34-
dc.identifier.issue35-
dc.identifier.spage8878-
dc.identifier.epage8886-
dc.identifier.isiWOS:000324783000004-
dc.publisher.placeNetherlands-

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