A developing heart valve, the generation of fibrotic heart tissue, and the formation of calcified aortic valve nodules all share a common component - activated fibroblasts. One source of activated fibroblasts is endothelial to mesenchymal transformation (EndMT), which is the differentiation of mature endothelial cells into mesenchymal cells. EndMT was first observed in embryonic heart valve development, but recent studies have shown that mesenchymal transformation can also occur in wound healing, cancer, cardiac fibrosis, and calcific aortic valve disease. The mechanisms and functional role of EndMT in adult applications, especially in response to tissue mechanics, have not been fully investigated. This award supports fundamental research on the role of mechanobiology on EndMT in aortic heart valves. Determining the cellular and tissue-level conditions that lead to EndMT, and how mesenchymally transformed cells promote disease, will provide an understanding of how aortic valves calcify and fill an unmet need in cardiovascular medicine. More broadly, this work will provide better methods for understanding fibrotic disease, cancer metastasis, and biomaterial design. This research requires expertise from several fields including tissue engineering, biomechanics, and computational biology; and this multidisciplinary approach will be integrated to promote graduate, undergraduate, and K-12 science and engineering education.
EndMT has been observed in human valves near calcified nodules, and factors present in aortic valve disease including inflammatory cytokines, pathological cyclic strain, and altered shear stress have individually been shown to induce cell transformation in adult aortic valve endothelial cells. Preliminary work has also shown that extracellular matrix composition mimicking diseased valve conditions strongly stimulates mesenchymal transformation and calcification. No studies to date have linked the degree of EndMT to valve calcification. The research team will engineer novel cell culture models and hybrid stochastic/continuum computational models to test the hypothesis that the activated fibroblasts generated from EndMT promote valve matrix remodeling, inflammatory cytokine release, and calcified nodule formation. The research objectives are to characterize the extracellular matrix-aortic valve endothelial cell interactions that impact EndMT and determine if mesenchymally transformed cells promote calcification, and to predict mesenchymally transformed cell evolution and growth using hybrid computational models. The long-term goal of this research program is to develop tools that can (1) determine the factors that promote or inhibit EndMT and its subsequent effects and (2) provide a platform for investigating therapeutic interventions, which could have a major impact on the technology available to scientists and lead to novel treatments for human disease.
