Abstract
Here we exploit keloid scars, a fibroproliferative skin disorder with no known cause or cure, to investigate this feature of fibrosis. We show that ECM alignment is mimicked in vitro by culturing fibroblasts isolated from the keloid dermis, and therefore, keloid fibroblasts (KDF) are used to investigate the cellular and mechanical drivers of fibrotic matrix alignment.KDF develop a significantly aligned supracellular actin network, mediated by cell-cell adhesions, that enable the formation of aligned ECM. We reveal that autocrine interleukin-6 (IL- 6) in keloid fibroblasts is both necessary and sufficient to induce this phenotype. Downstream of IL-6, independent pharmacological inhibition of ERK, AKT and STAT3, prevent cell alignment, highlighting a role for these signalling pathways in this fibrotic phenotype. Upstream of IL-6, although our data were inconclusive, we propose a role for c-Jun in the constitutive production of IL-6 in keloid fibroblasts.
Keloid fibroblasts also display aligned focal adhesions, which we hypothesise generate aligned traction forces that enable the anisotropic remodelling of the ECM. To examine patterns in tractions, traction force microscopy (TFM) was performed on KDF and NDF. No significant differences in traction alignment were found, highlighting that further optimisation may be required.
Overall, the work presented in this thesis suggests a novel function for IL-6 in keloid pathogenesis, as IL-6 signalling has been shown to be vital in cell and ECM remodelling. These data suggest that therapeutic targeting of IL-6 may not only reduce inflammation, but als
Date of Award | 1 Jan 2024 |
---|---|
Original language | English |
Awarding Institution |
|
Supervisor | Brian Stramer (Supervisor) & Tanya Shaw (Supervisor) |