טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMaizels Leonid
SubjectElectrophysiological Implications of Cardiomyocytes, Derived
from Human Pluripotent Stem Cells
DepartmentDepartment of Medicine
Supervisor Professor Lior Gepstein
Full Thesis textFull thesis text - English Version


Abstract

In the last decade, we have witnessed a rapid increase in the recognition and characterization of inherited arrhythmogenic disorders with major advances being made in our understanding of their underlying patho-physiological mechanisms, their natural history and their inheritance patterns. Salient examples for such arrhythmogenic disorders include the congenital long QT syndromes (LQTS), now classified into at least 12 different types based on the proteins being affected; and catecholaminergic polymorphic ventricular tachycardia (CPVT) which is associated with abnormal calcium handling in cardiomyocytes. Despite these significant advances, many questions remain regarding the patho-physiology of these disorders and their optimal treatment approaches. To advance our mechanistic understanding of these syndromes and to provide an experimental platform for evaluating potential disease modulators in a patient-specific manner, an in vitro source for human cardiac tissue displaying such arrhythmogenic syndromes is direly needed. The recently described induced pluripotent stem cell (iPSC) technology may offer a possible solution to this cell-sourcing problem. This groundbreaking approach is based on reprogramming of adult somatic cells (such as fibroblasts) into pluripotent stem cell lines by the ectopic expression of a set of transcription factors. The generated iPSC lines could then be coaxed to differentiate into a plurality of cell lineages including bona fide cardiomyocytes. In the current project, we hypothesize that the generation of patient-specific human iPSC (hiPSC) will allow the development of disease-specific in vitro models; yielding new patho-physiologic insights into genetic disorders and offering a unique platform to test novel therapeutic strategies. To this end, we established patient/disease-specific hiPSC models from patients inflicted with LQTS and CPVT. The generated healthy-control and diseased hiPSCs were differentiated into cardiomyocytes. The established LQTS hiPSC- and CPVT hiPSC-derived cardiac tissue models were investigated using detailed molecular, functional (intracellular and extracellular electrophysiological recordings) and pharmacological studies. These studies were designed to provide new insights into the mechanisms of arrhythmias in these syndromes, on patient-specific genotype-phenotype interactions, on the effects of potential disease modulators, and for screening of drugs that may potentially aggravate or ameliorate the disease phenotype, thereby demonstrating the potential of hiPSC-based disease models in advancing personalized medicine.