Kim, K. P.; Lemmon, C. A.

One of the main drivers of fibrotic diseases is epithelial-mesenchymal transition (EMT): a transdifferentiation process in which cells undergo a phenotypic change from an epithelial state to a pro-migratory state. The cytokine transforming growth factor-{beta}1 (TGF-{beta}1) has been previously shown to regulate EMT. TGF-{beta}1 binds to fibronectin (FN) fibrils, which are the primary extracellular matrix (ECM) component in renal fibrosis. We have previously demonstrated experimentally that inhibition of FN fibrillogenesis and/or TGF-{beta}1 tethering to FN inhibits EMT. However, these studies have only been conducted on 2-D cell monolayers, and the role of TGF-{beta}1-FN tethering in 3-D cellular environments is not clear. As such, we sought to develop a 3-D computational model of epithelial spheroids that captures both EMT signaling dynamics and TGF-{beta}1-FN tethering dynamics. We have incorporated the bi-stable EMT switch model developed by Tian et al. (2013) into a 3D multicellular model, capturing both temporal and spatial TGF-{beta}1 signaling dynamics. We show that the addition of TGF-{beta}1 affects cell proliferation, EMT progression, and cell migration. We then incorporate TGF-{beta}1-FN fibril tethering by locally reducing the TGF-{beta}1 diffusion coefficient as a function of EMT to simulate the reduced movement of TGF-{beta}1 when tethered to FN fibrils during fibrosis. We show that incorporation of TGF-{beta}1 tethering to FN fibrils promotes a partial EMT state, independent of exogenous TGF-{beta}1 concentration, indicating a mechanism by which fibrotic ECM can promote a partial EMT state.