AAV-mediated conversion of human pluripotent stem cell-derived pacemaker.

Patrick K W Chan, Lin Geng, Yi Gao, Wendy Keung, Ronald A Li

Biochemical and biophysical research communications 2017 Dec 09

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Malfunction of nodal pacemaker (Pm) cardiomyocytes (CMs) due to diseases or aging leads to rhythm generation disorders, necessitating electronic Pm implantation. We functionally reprogrammed human pluripotent stem cell (hPSC) derived-ventricular (V) CMs into -PmCMs via recombinant adeno-associated virus serotype 9 (rAAV9)-mediated overexpression of engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker has 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. Implantation of rAAV9-HCN1ΔΔΔ-based BPm in a preclinical porcine model of complete heart block significantly reduced the dependence on device-supported pacing and generated spontaneous heart rhythms from the BPm. Collectively, these results have further laid the groundwork on BPm for future translation. Copyright © 2017 Elsevier Inc. All rights reserved.

Citation

Patrick K W Chan, Lin Geng, Yi Gao, Wendy Keung, Ronald A Li. AAV-mediated conversion of human pluripotent stem cell-derived pacemaker. Biochemical and biophysical research communications. 2017 Dec 09;494(1-2):346-351