Most deadly diseases, and particularly cardiovascular diseases, occur more often in older people, with age being the primary risk factor. Therefore, an urgent need exists for a better understanding of disease progress in aged tissues in order to find ways to decrease age-related problems. This project focuses on establishing a unique tissue engineered model system of the aging human myocardium that can be used to investigate the role of the aging tissue microenvironment on cell survival after a heart attack/myocardial infarction (MI). The novel model overcomes limitations 1) of animal models that have limited applicability to the human condition and involve complex systems with difficult to control parameters and 2) of cell culture models that are oversimplified. Studies are designed to test the hypothesis that the aging tissue microenvironment (i.e., biochemical composition and biophysical properties such as stiffness of the extracellular matrix (ECM)) affects cell survival after MI, and the decreased cellular communication due to cellular damage is the cause of increased cell death in older tissues. Research and education are integrated through undergraduate and graduate training and mentoring activities and a three-day summer workshop titled "Peace through Science" that aims to leverage science to teach tolerance and inclusion.
As part of the long-term career goal to establish a research program focused on biomimetic engineered model tissues to investigate the multicellular communication and cell-microenvironment interactions in healthy and diseased tissues, the focus of this project is the first study to demonstrate that tissue engineering and microfabrication can create highly impactful aging-mimicking disease models and that these models can be used to elucidate the role of aging on a specific disease--myocardial infarction. Specific hypotheses to be tested are: 1) matrix age affects cell survival due to altered biochemical and biophysical matrix content by age, 2) chronological age of cells affects cell survival due to altered paracrine factor secretion by the cells by age and 3) cellular damage that accumulates by age in myocardial tissue causes decreased cellular function and interaction, resulting in increased cell death upon MI in older tissues. The related research objectives are to 1) create an aging mimicking myocardial model tissue that can be used to simulate MI conditions and 2) study the effect of the aging tissue microenvironment on cell survival upon MI. The engineered myocardial tissue model will be microfabricated using human induced pluripotent stem cell-derived endothelial and myocardial cells, biomimetic hydrogels and microfluidics. Cellular communication will be studied under MI-mimicking conditions (i.e., hypoxia, nutrient starvation, reperfusion and oxidative stress.) The knowledge gained using this model tissue will unravel the cellular communication within normal, aging and diseased myocardium and will shed light on both the cell-level phenomena upon MI and on the nature of aging itself. As only 10% of therapies that are shown to be successful in animal models pass clinical trials, engineered tissue models using human cells are gaining much interest due to their advantages over animal models and their potential to increase clinical translation of basic science by filling the gap between in vitro and in vivo studies.
