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Title page for ETD etd-11182015-125322


Type of Document Dissertation
Author Feaster, Tromondae Kenta
URN etd-11182015-125322
Title Implementation of human-induced pluripotent stem cell-derived cardiomyocyte to model excitation-contraction coupling in health and disease
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Joey V. Barnett Committee Chair
Björn C. Knollmann Committee Member
Charles C. Hong Committee Member
Dan M. Roden Committee Member
H. Scott Baldwin Committee Member
Keywords
  • excitation-contraction coupling
  • stem cell-derived cardiomyocyte
Date of Defense 2015-11-05
Availability unrestricted
Abstract
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have the potential to be an important tool for cardiovascular disease modeling, pre-clinical cardiotoxicity evaluation, and drug discovery. However, detailed studies of their excitation-contraction (EC) coupling are limited by the lack of appropriate methodology. Here, I set out to investigate the EC coupling of normal and diseased hiPSC-CMs and compare the results to that of adult ventricular CMs (i.e., rabbit and mouse) under identical experimental conditions. I found that hiPSC-CMs display relatively mature EC coupling properties (i.e., electrophysiology, Ca handling and contractility). To assess their contractile properties I have developed a novel culture method that enables robust contractile measurements of single hiPSC-CMs. I discovered that hiPSC-CMs display contractile properties comparable to that of adult rabbit CMs, including comparable contraction kinetics. Moreover, EC coupling properties were comparable across hiPSC-CM lines generated at different institutions and post recovery from cryopreservation. Using disease specific hiPSC-CMs I revealed that HCM MYH7 R633H hiPSC-CMs display contractile abnormalities, and I provided evidence supporting an enhanced myofilament Ca sensitivity mechanism. Furthermore, I demonstrated hiPSC-CMs display a robust response to pharmacological stimuli including the myofilament Ca sensitizer EMD57033. These findings will aid functional studies of disease specific hiPSC-CMs as well as the effects of novel and known pharmacological agents.
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