Mechanobiology of Myofibroblast Behavior in Health and Disease

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The heart is made up of different types of cells. Myofibroblasts develop through a transformation from normally occurring fibroblasts. Myofibroblasts play a critical role in physiological and pathophysiological events such as heart valve development, the generation of fibrotic heart tissue, and the formation of calcified aortic valve nodules. These activated cells are able to proliferate, secrete inflammatory and tissue-degrading chemical factors, and remodel the surrounding environment such as the extracellular matrix (ECM). Endothelial to mesenchymal transformation (EndMT), which is the transition of endothelial cells to mesenchymal-like cells, is one source of myofibroblasts. EndMT was first observed in embryonic heart valve development, but more recent studies have shown that EndMT is also observed in tissue-level repair processes -- such as wound healing -- and in adult disease development -- including cancer, cardiac fibrosis, and calcific aortic valve disease (CAVD). Changes in the endothelial cell mechanical and chemical environment can promote EndMT, but less is known about why these transformed cells can promote tissue regeneration or progression of disease. A primary research goal of this project, which combines experimental and computational modeling methods, is to determine if and how combined mechanical and chemical forces seen in the normal physiological environment direct mesenchymally transformed aortic valve endothelial cells toward disease. The research results will be incorporated into workshops that are designed to enhance K-12 scientific and technological understanding, and this award will also provide graduate and undergraduate educational and professional development opportunities.The project will test how the composition of the extracellular environment and shear stresses, which occur in vivo due to blood flow, affect mesenchymally-transformed cell behavior in laboratory experiments (in vitro). Additionally, the project will use mathematical modeling and computer simulation to study the ability of EndMT-derived myofibroblasts to restructure the surrounding tissue, their interaction with resident valve interstitial cells, the molecular mechanisms directing these behaviors, and the potential feedback loop of these multiscale mechanisms. This research combines experiments using microfluidic cell culture models of the aortic valve with computational simulation of the transformation, interaction, and migration of cells under different mechanical and chemical environmental conditions. Both the experimental and computational models will mimic cell-cell and cell-ECM interactions in the body, including cell growth, migration, proliferation, and interaction in both healthy and diseased aortic valves. The computational model simulations will enable a more detailed examination of the mechanical and chemical factors most critical to disease progression and provide a means to probe the feedback loop of EndMT and tissue modification, which can only be performed in a limited manner experimentally. Together, the in vitro experiments and computational simulations will provide new insight into the molecular mechanisms of CAVD, illuminate the mechanical conditions that lead to regenerative or pathological tissue remodeling, and provide a test-bed for new therapeutic strategies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.