Investigating TGF-β1-induced renal fibrosis in a parallel computational-experimental spheroid system.

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Citation abstract

Epithelial-mesenchymal transition (EMT) drives tubular atrophy and extracellular matrix (ECM) remodeling during renal fibrosis. The cytokine transforming growth factor-beta 1 (TGF-β1) is a major regulator of EMT and other profibrotic cell processes that drive renal fibrosis. TGF-β1 signaling is upregulated in response to increased assembly of the ECM protein fibronectin (FN), creating a positive feedback loop that promotes chronic EMT and ECM remodeling. Investigating the role of TGF-β1-FN cross talk in driving tubule damage is not easily probed via animal models or clinical investigations. Additionally, the effects of renal fibrosis on the 3D organization and polarization of the renal tubule are not easily studied using traditional 2D cell assays. To address these shortcomings, we have developed a combined computational-in vitro approach to investigate spatial and temporal effects of TGF-β1-FN cross talk in 3D spheroid models of tubular epithelial cells. Results from this study demonstrated that a computational agent-based model (ABM) of renal fibrosis captured tubular atrophy and localized ECM remodeling in response to TGF-β1. Furthermore, simulations from the ABM predicted that inhibiting ECM assembly would block tubular atrophy and dilation. In vitro experiments were then conducted using 3D renal epithelial spheroids; these confirmed ABM predictions and demonstrated that inhibiting FN assembly ameliorated TGF-β1-induced dilation of 3D tubular epithelial cell spheroids.