Annually, about 25,000 newborns in the United States are born with a congenital heart defect. In some cases only regular check-ups by a cardiologist are required; in others, defects are much more serious and require lifelong medication, implantation of a pacemaker, and/or multiple surgeries. In my proposed research, I will engineer a novel three-dimensional (3D) in vitro model of developing human heart tissue using bioactive hydrogels and human induced pluripotent stem cells (hiPSCs). My proposed 3D in vitro model of the developing human heart tissue will facilitate more complex and physiologically relevant cell-cell and cell-matrix interactions than two-dimensional cell culture, while allowing for higher throughput experiments than would be possible using animal models. Until now, the causes of congenital heart defects are only partially understood, particularly in the absence of genetic mutations. The developing heart arises from cells in the mesoderm which differentiate into various cell types including cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. It has been shown that differentiation of stem cells is greatly influenced by the production of extracellular matrix (ECM), which is the basis and supporting material for the developing heart cells. The aims of my proposal are to therefore: (1) characterize the relationship between expression of genes implicated in congenital heart defects and the expression of genes for cardiac markers and ECM production by hiPSCs differentiating into cardiac cells and (2) assess differentiation of hiPSCs within my degradable 3D engineered tissue and characterize changes in gene expression and ECM production when exposed to chemicals known to cause congenital heart defects. Human iPSCs can be differentiated into cardiac cells following protocols that take advantage of the known signaling pathways used in cardiac development. These sequential differentiation steps follow a similar path to that taken by cells in the developing heart. My proposed research therefore investigates the hypothesis that this in vitro model of the developing human heart can be used to identify factors involved in the formation of congenital heart defects. This highly innovative approach, once validated, has the potential to help identify the causes of congenital heart defects.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2013 → 12/31/2014|