A comparative study investigating the effects of different methodologies on the maturation of human induced pluripotent stem cell derived cardiomyocytes

Abstract

Introduction: Despite important contributions to our understanding, animal models do not reliably recapitulate human cardiac physiology or the disease complexity of cardiac channelopathies. The development of human induced pluripotent stem cells (hiPSCs) has provided an unprecedented opportunity to generate a cell-based model for human diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT); an inherited cardiac channelopathy, predominantly caused by mutations in the RYR2 gene, that can predispose the heart to life-threatening, adrenergically mediated arrhythmic activity. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) harbour an immature phenotype, limiting their implementation as physiologically relevant in vitro disease models. Aim: To generate hiPSC-CMs with a greater degree of maturity, thus physiological relevance, for assessing the CPVT disease phenotype and pharmacological treatments by incorporating reported hiPSC-CM maturation approaches into the cardiomyocyte differentiation protocol. Methods and results: The small-molecule based directed differentiation of hiPSC-CMs was optimised for the RYR2 patient cell line. Four hiPSC-CM maturation approaches were then evaluated. Prolonged culture, and thyroid (T3) and glucocorticoid (Dex) hormone supplementation significantly upregulated �1-adrenergic receptor expression (p

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Luigi Venetucci (Supervisor)