DOI
https://doi.org/10.25772/4V89-WP27
Author ORCID Identifier
https://orcid.org/0000-0002-2112-9722
Defense Date
2025
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Christopher Lemmon
Second Advisor
Rebecca Heise
Third Advisor
Priscilla Hwang
Fourth Advisor
Seth Weinberg
Fifth Advisor
Mark Okusa
Abstract
Irreversible damage to tubules is a main marker of end-stage renal fibrosis. One of the main processes suggested to drive this irreversible damage is epithelial-mesenchymal transition, where tubular epithelial cells lose cell adhesivity and acquire mesenchymal traits like increased migratory capacity and loss of apicobasal polarity. The cytokine transforming growth factor-beta 1 (TGF-β1) is a major regulator of profibrotic cell processes like EMT. TGF-β1 signaling is upregulated in response to increased assembly of the extracellular matrix protein Fibronectin, creating a positive feedback loop that promotes chronic EMT and ECM remodeling.
This work proposes an important role of FN fibril assembly in driving renal fibrosis through increased TGF-β1 tethering around cells that promotes profibrotic processes. Investigating the role of TGFB1-FN crosstalk 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 probed using traditional 2D cell assays. To address these shortcomings, we have developed a combined computational and in vitro approach to investigate spatial and temporal effects of TGF-β1-Fibronectin crosstalk in 3D spheroid models of tubular epithelial cells. Our results suggest that EMT is dependent on increased TGF-β1 localization around cells, FN fibril assembly upregulates TGF-β1 signaling, and direct FN fibril assembly and TGF-β1 production by surrounding mesenchymal cells also contributes to EMT progression. These studies provided important insight on spatial and temporal changes in TGF-β1-FN crosstalk that drive the progression of renal fibrosis.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-3-2025