All ETDs from UAB

Advisory Committee Chair

Palaniappan Sethu

Advisory Committee Members

Vladimir Fast

Tariq Hamid

Ho-Wook Jun

Joanne Murphy-Ullrich

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Every year about 735,000 Americans will suffer a heart attack and 1 in 4 will end up dying from heart disease. Study of this disease has been impacted by the limited availability of appropriate human cell types. The discovery of human induced pluripotent stem cells (hiPSCs) and development of protocols to differentiate these cells into cardiomyocytes (hiPSC-CM) has enabled study into this disease free from ethical dilemma, and reliance on animal models. Unfortunately, hiPSC-CMs are immature in nature and closely resemble fetal or neonatal cardiomyocytes. We hypothesized that hemodynamic stimuli, missing from static cultures, would allow us to mature hiPSC-CMs closer to an adult phenotype. We used the Biomimetic Cardiac Tissue Model (BCTM), which is able to reproduce the cardiac hemodynamics associated with any stage of the development including cardiogenesis, adult, and disease. The BCTM allowed us to study the effects of hemodynamics on the maturation of hiPSC-CMs. Our initial studies investigated hiPSC-CM survival under hemodynamic loads. It was discovered that nutrient supply and the application rate of hemodynamic loads are critical factors in the survival of hiPSC-CMs under stress. This lesson was applied to our second attempt where we limited the hemodynamics to levels seen during early cardiogenesis. We discovered that by applying hemodynamic stimulation to early hiPSC-CMs we can induce physiological hypertrophy and increase fractional shortening after only one week of stimulation. A second limitation of current cardiovascular research is the lack of in vitro models of two widespread forms of heart disease, hypertrophic and dilated cardiomyopathy. Using an established myoblast cell line (H9c2 cells) we were able to reproduce the essential characteristics of each disease state. After 48 hours we found fibrotic remodeling of the extracellular matrix (ECM), evidence for increases in reactive oxygen species, changes to cellular aspect ratio, and damage to critical cytoskeletal proteins linked to disease in vivo. Each of these findings corresponded appropriately to similar disease outcomes measured in vivo. Together, these studies demonstrate that the BCTM can be used to successfully apply hemodynamic loads to cardiac cell types to create developmental models of cardiogenesis and disease models of hypertrophic and dilated cardiomyopathy.

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