Subcellular Mechanics Regulates Structure and Function of Neonatal and Stem Cell Derived Cardiomyocytes
thesisposted on 21.07.2015, 00:00 by Elina Sarmah
According to the American Heart Association, approximately one-third of deaths in the US are caused by cardiovascular disease. In cardiac disease, variations in contractility and sarcomere assembly in cardiomyocytes occur in response to increased external load. These changes occur at the subcellular level to maintain the internal balance of forces along the length and width of the cell. This study presents the use of BioMEMS microtopography substrates fabricated from stiffness-tunable elastic material to demonstrate how remodeling affects contractility and assembly at the subdomain level of cardiomyocytes. These experiments lead to a better understanding of the structure and function of heart muscle, and the techniques used can be applied in clinical research involving human diseases with cardiomyocytes. The second part of this study involves cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from affected patients that carried a cTnT R173W point mutation to examine their functional characteristics during early and late development, as compared to iPSC-CMs from normal family members. The cells were also treated with 200 nM dose of a calcium sensitizing drug, Omecamtiv Mecarbil, to test whether this drug could therapeutically rescue the mutation cells during its development stage to a normal physiological range. In all, this investigation shows that the use of bioengineering techniques can provide a unique approach for micromechanical analysis of cardiomyocytes, and provides insight to the treatment of patients suffering from heart disease.