Interactions of Cardiomyocytes and Myofibroblasts: An Experimental and Theoretical Model Study

OF THE THESIS Interactions of Cardiomyocytes and Myofibroblasts: An Experimental and Theoretical Model Study by Teresa M. Abney Doctor of Philosophy in Mechanical Engineering Washington University in St. Louis, 2012 Research Advisor: Professor Guy Genin Cardiomyocytes and fibroblasts make up the majority of cells in natural myocardium. While cardiomyocytes are primarily responsible for the mechanical contraction, fibroblasts are responsible for maintaining the extracellular matrix and tissue compliance. In response to pathologies such as hypertension or infarction, fibroblasts in the heart can convert to myofibroblasts, a larger and more contractile phenotype between a fibroblast and a smooth muscle cell. Myofibroblasts are essential to wound healing, but can change the compliance and functioning of heart tissue and can produce pathological fibrosis, formation of excess fibrous connective tissue. In developing therapeutic approaches it is essential to understand how myofibroblasts modulate the electromechanical functions of fibrotic heart. In this dissertation, the problem was approached by developing computational and experimental models of heart muscle with varying proportions of mFBs to CMs randomly distributed. The experimental model consists of engineered heart tissue (EHT) assembled from embryonic cardiomyocytes and containing defined fractions of myofibroblasts randomly distributed throughout ii the tissue. The computational model is formulated at the cellular level taking into account individual cardiomyocytes and myofibroblasts to yield the pattern of impulse spread as modulated by the presence of myofibroblasts acting either as insulators or resistors. The excitatory impulse activates the contraction of individual viscoelastic cells that are mechanically linked to other cells and the extracellular matrix. The results give insight into the mechanical and electrical modulation of EHT by myofibroblasts.