Year: 2020
Type: dissertation
Abstract: Ischemic heart disease remains the number one killer worldwide, and no therapies are aimed at restoring lost muscle within patients’ hearts. Human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) demonstrate engraftment and mediate beneficial effects on left ventricular contractile function in rodent and non-human primate models. Unfortunately, ventricular arrhythmias in large animal models post-transplantation prevent their clinical application. Loss of connexin-43 (Cx43) gap junctions (GJs) is hypothesized to contribute to hPSC-CM induced arrhythmias. Phosphomimetic mutations at casein kinase 1 (CK1) targeted residues that mimic the phosphorylated state of Cx43 reduced ischemia induced GJ remodeling and susceptibility to inducible arrhythmias in mice. hESC-CMs heterozygous for these CK1 mutations displayed ischemia resistant Cx43 GJs by immunofluorescence but were not protected from ischemia induced reentrant arrhythmias. Discovery of a frameshift mutation and a heterozygous genotype motivated production of homozygous CK1 hESC clones that merits further investigation as a potential solution to hPSC-CM graft-related arrhythmias.
Source: TSpace (University of Toronto)
Author: Joseph Jargstorf
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3093901469