Vigor, Charlotte Jayne; (2006) Switching off the fibroproliferative phase of wound healing: an investigation of the normal mechanisms and pathological scar-related defects. Doctoral thesis , UCL (University College London).

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Abstract

Using in vitro models that mimic various aspects/stages of wound healing, this thesis attempted to define the events that lead to the culmination of the fibro-proliferative phase of wound healing, i.e. apoptosis and any potential defects exhibited by keloid scars. Normal scar-derived fibroblasts were found to undergo apoptosis in contractile collagen gels, whereas keloid fibroblasts did not. Investigation of the mechanisms involved indicated that this form of apoptosis required both the three-dimensional and collagenous nature of the gel and was not simply caused by removal of tension, but required biochemical cues. Collagen-contraction-induced apoptosis was found to require matrix metalloproteinase (MMP) and autocrine transforming growth factor-P (TGF-p) activity. Indeed contraction was accompanied by significantly increased expression and activation of MMPs along with indications of increased matrix breakdown. Furthermore, pure products of matrix breakdown significantly induced apoptosis of normal scar cell monolayers. The defect exhibited by keloid fibroblasts was found to be specific to that induced during collagen contraction since they were equivalent to normal scar cells in their sensitivity to other forms of apoptosis induction and demonstrated normotrophic p53 stabilisation and activation of PARP (Poly(ADP-ribose)polymerase) and caspase-3. During collagen contraction, keloid fibroblasts failed to produce biochemical cues of apoptosis and although they exhibited normal levels of MMP gene expression and activation, they failed to breakdown collagen gels. However, these cells did undergo apoptosis in response to the biochemical cues produced on normal scar cell contraction of collagen gels, but surprisingly could not respond to pure forms of matrix breakdown products. Unlike normal scar cells, keloid fibroblasts failed to differentiate into myofibroblasts in collagen gels. The addition of exogenous TGF-pl was found to restore differentiation and furthermore allowed the cells to undergo apoptosis in collagen gels. Surprisingly, TGF-pl also restored the ability of keloid cells to undergo apoptosis in response to matrix breakdown products.

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