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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-beta1 (TGF-beta1) has been previously shown to regulate EMT. TGF-beta1 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-beta1 tethering to FN inhibits EMT. However, these studies have only been conducted on 2-D cell monolayers, and the role of TGF-beta1-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 captured both EMT signaling dynamics and TGF-beta1-FN tethering dynamics. We have incorporated the bi-stable EMT switch model developed by Tian et al. (2013) into a 3-D multicellular model to capture both temporal and spatial TGF-beta1 signaling dynamics. We showed that the addition of increasing concentrations of exogeneous TGF-beta1 led to faster EMT progression, indicated by increased expression of mesenchymal markers, decreased cell proliferation and increased migration. We then incorporated TGF-beta1-FN fibril tethering by locally reducing the TGF-beta1 diffusion coefficient as a function of EMT to simulate the reduced movement of TGF-beta1 when tethered to FN fibrils during fibrosis. We showed that incorporation of TGF-beta1 tethering to FN fibrils promoted a partial EMT state, independent of exogenous TGF-beta1 concentration, indicating a mechanism by which fibrotic ECM can promote a partial EMT state.
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Computational models of migration modes improve our understanding of metastasis
Tumor cells migrate through changing microenvironments of diseased and healthy tissue, making their migration particularly challenging to describe. To better understand this process, computational models have been developed for both the ameboid and mesenchymal modes of cell migration. Here, we review various approaches that have been used to account for the physical environment's effect on cell migration in computational models, with a focus on their application to understanding cancer metastasis and the related phenomenon of durotaxis. We then discuss how mesenchymal migration models typically simulate complex cell–extracellular matrix (ECM) interactions, while ameboid migration models use a cell-focused approach that largely ignores ECM when not acting as a physical barrier. This approach greatly simplifies or ignores the mechanosensing ability of ameboid migrating cells and should be reevaluated in future models. We conclude by describing future model elements that have not been included to date but would enhance model accuracy.
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- PAR ID:
- 10584290
- Publisher / Repository:
- American Institute of Physics
- Date Published:
- Journal Name:
- APL Bioengineering
- Volume:
- 4
- Issue:
- 4
- ISSN:
- 2473-2877
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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