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postgraduate thesis: Engineered anisotropy of human embryonic stem cell-derived ventricular cardiomyocytes by physical alignment for enhanced safety and accuracy of arrhythmogenicity prediction

TitleEngineered anisotropy of human embryonic stem cell-derived ventricular cardiomyocytes by physical alignment for enhanced safety and accuracy of arrhythmogenicity prediction
Authors
Issue Date2015
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wang, J. [王嘉顯]. (2015). Engineered anisotropy of human embryonic stem cell-derived ventricular cardiomyocytes by physical alignment for enhanced safety and accuracy of arrhythmogenicity prediction. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558994
AbstractHuman (h) pluripotent stem cells such as embryonic stem cells (ESC) can be directed into the cardiac lineage, representing a potential unlimited source of cardiomyocytes (CMs) for myocardial repair. However, their arrhythmogenicity has not been thoroughly assessed. Indeed, native ventricular (V) CMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions. However, hESC-derived CM (hESC-CM) clusters are randomly organized. Using shrink-film microgroove technology, hESC-VCMs derived using a specification protocol were seeded on micro-fabricated polydimethylsiloxane (PDMS) consisting of multi-scale (nano to micro) grooves to induce cell alignment, followed by high-resolution optical mapping recordings. Aligned preparations consistently showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resulting in significantly higher anisotropy ratios (AR=LCV/TCV) compared to unaligned controls (1.8-2.0 vs. 1.0). AR depended on the topography but cellular properties such as action potential duration (APD) were not altered by alignment. Importantly, the total incidence of spontaneous and inducible arrhythmias, in the form of functional reentrant spiral waves, during steady-state pacing and programmed electrical stimulations (S1-S2), respectively, was significantly reduced from 57% in controls to 17-23% in aligned preparations. In controls, isoproterenol application promoted reentrant arrhythmias, which was inhibited by cell alignment. Multi-scale topography enables the physical alignment of hESC-VCMs, thereby reproducing functional anisotropy. Aligned anisotropic hESC-VCMs are less susceptible to arrhythmias, and may lead to future transplantable prototypes with improved efficacy and safety as well as more accurate models for arrhythmogenicity screening.
DegreeDoctor of Philosophy
SubjectStem cells
Heart cells
Dept/ProgramPhysiology
Persistent Identifierhttp://hdl.handle.net/10722/216240

 

DC FieldValueLanguage
dc.contributor.authorWang, Jiaxian-
dc.contributor.author王嘉顯-
dc.date.accessioned2015-09-08T23:11:30Z-
dc.date.available2015-09-08T23:11:30Z-
dc.date.issued2015-
dc.identifier.citationWang, J. [王嘉顯]. (2015). Engineered anisotropy of human embryonic stem cell-derived ventricular cardiomyocytes by physical alignment for enhanced safety and accuracy of arrhythmogenicity prediction. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558994-
dc.identifier.urihttp://hdl.handle.net/10722/216240-
dc.description.abstractHuman (h) pluripotent stem cells such as embryonic stem cells (ESC) can be directed into the cardiac lineage, representing a potential unlimited source of cardiomyocytes (CMs) for myocardial repair. However, their arrhythmogenicity has not been thoroughly assessed. Indeed, native ventricular (V) CMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions. However, hESC-derived CM (hESC-CM) clusters are randomly organized. Using shrink-film microgroove technology, hESC-VCMs derived using a specification protocol were seeded on micro-fabricated polydimethylsiloxane (PDMS) consisting of multi-scale (nano to micro) grooves to induce cell alignment, followed by high-resolution optical mapping recordings. Aligned preparations consistently showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resulting in significantly higher anisotropy ratios (AR=LCV/TCV) compared to unaligned controls (1.8-2.0 vs. 1.0). AR depended on the topography but cellular properties such as action potential duration (APD) were not altered by alignment. Importantly, the total incidence of spontaneous and inducible arrhythmias, in the form of functional reentrant spiral waves, during steady-state pacing and programmed electrical stimulations (S1-S2), respectively, was significantly reduced from 57% in controls to 17-23% in aligned preparations. In controls, isoproterenol application promoted reentrant arrhythmias, which was inhibited by cell alignment. Multi-scale topography enables the physical alignment of hESC-VCMs, thereby reproducing functional anisotropy. Aligned anisotropic hESC-VCMs are less susceptible to arrhythmias, and may lead to future transplantable prototypes with improved efficacy and safety as well as more accurate models for arrhythmogenicity screening.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshStem cells-
dc.subject.lcshHeart cells-
dc.titleEngineered anisotropy of human embryonic stem cell-derived ventricular cardiomyocytes by physical alignment for enhanced safety and accuracy of arrhythmogenicity prediction-
dc.typePG_Thesis-
dc.identifier.hkulb5558994-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePhysiology-
dc.description.naturepublished_or_final_version-

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