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Conference Paper: Functional reprogramming of human embryonic stem cell-derived ventricular cardiomyocytes into bio-artificial pacemaker

TitleFunctional reprogramming of human embryonic stem cell-derived ventricular cardiomyocytes into bio-artificial pacemaker
Authors
Issue Date2015
Citation
The 2015 Annual Meeting of the International Society for Stem Cell Research (ISSCR 2015), Stockholm, Sweden, 24-27 June 2015. How to Cite?
AbstractNormal heart rhythms originate in the sino-atrial node, a specialized cardiac tissue consisting of only a few thousands nodal pacemaker (Pm) cardiomyocytes (CMs). Malfunction of PmCMs due to diseases or aging leads to rhythm generation disorders, necessitating the implantation of electronic Pm, with such shortcomings as limited battery life, permanent implantation of leads, lead dislodging (particularly to pediatric patients due to somatic growth), the lack of autonomic responses, etc. As such, the engineering of bio-artificial Pm (BPm) as an alternative or supplement to electronic devices has been pursued. Human pluripotent stem cell (hPSC) can self-renew and differentiate into all lineages, serving as an unlimited CM source. However, the yield of PmCMs is always typically poor (<3%), independent of hPSC lines and even with directed cardiac differentiation protocols; recently, we reported a highly efficient hPSC specification protocol, enabling mass generation of ventricular (V) CMs with ~100% yield and purity. Building upon our series of previous studies of the crucial PmCM protein hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), here we functionally reprogrammed hPSC-VCMs into -PmCMs via adeno-associated virus (rAAV9, isoform chosen for cardiac tropism)-mediated overexpression of the engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker residues 246-248 have been strategically deleted by design to promote cardiac pacemaking. rAAV9-HCN1ΔΔΔ-reprogrammed hPSC-PmCMs converted from -VCMs showed automaticity and action potential parameters typical of native nodal PmCMs. When tested in a long-term preclinical large animal porcine model of complete heart block (via atrio-ventricular node radiofrequency ablation), implantation of rAAV9-HCN1ΔΔΔ-based BPm via focal injection in the right ventricle significantly reduced the dependence on device-supported pacing from 89% observed in sham to 12% of our tested subjects. Electro-anatomical mapping further revealed the generation of spontaneous heart rhythms from the BPm, which remained stable for at least 4 weeks. Collectively, these results have taken our previous groundwork on BPm to the next translational level. Toxicity data collection for IND and the launch of a possible first-in-man trial of BPm are forthcoming.
DescriptionConference Theme: An Unveiling of Stem Cell Innovation
Posters - Cardiac Cells: no. F-1102
Persistent Identifierhttp://hdl.handle.net/10722/234408

 

DC FieldValueLanguage
dc.contributor.authorChan, KWP-
dc.contributor.authorGeng, L-
dc.contributor.authorGao, RY-
dc.contributor.authorKeung, WWY-
dc.contributor.authorHajjar, RJ-
dc.contributor.authorLi, RA-
dc.date.accessioned2016-10-14T13:46:41Z-
dc.date.available2016-10-14T13:46:41Z-
dc.date.issued2015-
dc.identifier.citationThe 2015 Annual Meeting of the International Society for Stem Cell Research (ISSCR 2015), Stockholm, Sweden, 24-27 June 2015.-
dc.identifier.urihttp://hdl.handle.net/10722/234408-
dc.descriptionConference Theme: An Unveiling of Stem Cell Innovation-
dc.descriptionPosters - Cardiac Cells: no. F-1102-
dc.description.abstractNormal heart rhythms originate in the sino-atrial node, a specialized cardiac tissue consisting of only a few thousands nodal pacemaker (Pm) cardiomyocytes (CMs). Malfunction of PmCMs due to diseases or aging leads to rhythm generation disorders, necessitating the implantation of electronic Pm, with such shortcomings as limited battery life, permanent implantation of leads, lead dislodging (particularly to pediatric patients due to somatic growth), the lack of autonomic responses, etc. As such, the engineering of bio-artificial Pm (BPm) as an alternative or supplement to electronic devices has been pursued. Human pluripotent stem cell (hPSC) can self-renew and differentiate into all lineages, serving as an unlimited CM source. However, the yield of PmCMs is always typically poor (<3%), independent of hPSC lines and even with directed cardiac differentiation protocols; recently, we reported a highly efficient hPSC specification protocol, enabling mass generation of ventricular (V) CMs with ~100% yield and purity. Building upon our series of previous studies of the crucial PmCM protein hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), here we functionally reprogrammed hPSC-VCMs into -PmCMs via adeno-associated virus (rAAV9, isoform chosen for cardiac tropism)-mediated overexpression of the engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker residues 246-248 have been strategically deleted by design to promote cardiac pacemaking. rAAV9-HCN1ΔΔΔ-reprogrammed hPSC-PmCMs converted from -VCMs showed automaticity and action potential parameters typical of native nodal PmCMs. When tested in a long-term preclinical large animal porcine model of complete heart block (via atrio-ventricular node radiofrequency ablation), implantation of rAAV9-HCN1ΔΔΔ-based BPm via focal injection in the right ventricle significantly reduced the dependence on device-supported pacing from 89% observed in sham to 12% of our tested subjects. Electro-anatomical mapping further revealed the generation of spontaneous heart rhythms from the BPm, which remained stable for at least 4 weeks. Collectively, these results have taken our previous groundwork on BPm to the next translational level. Toxicity data collection for IND and the launch of a possible first-in-man trial of BPm are forthcoming.-
dc.languageeng-
dc.relation.ispartofAnnual Meeting of the International Society for Stem Cell Research, ISSCR 2015-
dc.titleFunctional reprogramming of human embryonic stem cell-derived ventricular cardiomyocytes into bio-artificial pacemaker-
dc.typeConference_Paper-
dc.identifier.emailChan, KWP: pazhi@hku.hk-
dc.identifier.emailGeng, L: genglin@hku.hk-
dc.identifier.emailGao, RY: ryanko@hku.hk-
dc.identifier.emailKeung, WWY: wkeung@hku.hk-
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hk-
dc.identifier.authorityKeung, WWY=rp01887-
dc.identifier.authorityLi, RA=rp01352-
dc.identifier.hkuros268237-

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