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  • Fibrotic extracellular matrix preferentially induces a partial Epithelial–Mesenchymal Transition phenotype in a 3-D agent based model of fibrosis

This content will become publicly available on March 1, 2026

Title: Fibrotic extracellular matrix preferentially induces a partial Epithelial–Mesenchymal Transition phenotype in a 3-D agent based model of fibrosis
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.  more » « less
Award ID(s):
2302580
PAR ID:
10603942
Author(s) / Creator(s):
;
Publisher / Repository:
Elsevier
Date Published:
Journal Name:
Mathematical Biosciences
Volume:
381
Issue:
C
ISSN:
0025-5564
Page Range / eLocation ID:
109375
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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