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Assessing the mechanisms of defective TGF-β1 response in chronic wound fibroblasts

Morris, Nathanael Glyn 2018. Assessing the mechanisms of defective TGF-β1 response in chronic wound fibroblasts. PhD Thesis, Cardiff University.
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Abstract

Chronic wounds are regarded as skin wounds that fail to heal. Their chronic nature and requirement for long term treatment put a large financial burden on the healthcare providers. Prevalence of chronic wounds increases with age and is associated with diabetes; both of these are on the increase in western populations. This makes chronic wound research essential in order to understand the basic biological causes and identify potential therapeutic targets. The aim of this thesis was to characterise the response of chronic wound fibroblasts (CWFs) in response to Transforming Growth Factor β-1 (TGF-β1) stimulation, the cytokine responsible for fibroblast to myofibroblast differentiation. This differentiation is lost in chronic wounds, resulting in the loss of wound closure. TGF-β1 signals through two independent yet collaborating pathways: the classical TGF-βR and the non-classical HA-CD44-EGFR pathway. I aimed to explore the possible dysfunctional signalling in these pathways that may contribute to the loss of myofibroblast formation in CWFs. HAS1 was shown to have a higher basal expression of in CWFs, with increasing expression in response to TGF-β1. Altered HASs expression indicated a possible defective HA-CD44-EGFR pathway. HA pericellular coat formation, essential for normal dermal fibroblasts (NFs) differentiation, was lost in CWFs. This loss was found to be caused by the loss of CD44-EGFR co-localisation in CWFs. In CWFs, the EGFR was localised in a perinuclear location surrounded by a lipid envelope. Lipid localisation was associated with lysosomal staining indicating a possible role of a defective lipid metabolism or defective intracellular protein degradation pathways in CWFs. This data suggests that the non-classical pathway is the primary pathway responsible for the loss of myofibroblast formation. However, there are several factors that may contribute to this loss. Future research is required to pin-point the key players leading to aberrant protein, HA and lipid localisation in CWFs.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Funders: Health and Care Research Wales
Date of First Compliant Deposit: 1 October 2018
Last Modified: 01 Oct 2018 11:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/115346

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