Keloids are benign hyper-proliferative growths of fibrous tissue, where increased fibroblast
activity results in abnormal collagen deposition. Scientific literature related to the morphological
features of keloids especially at an ultrastructural level is outdated. Therefore the aim of this
study was to reassess present knowledge of the ultrastructural features of keloids and possibly
through this process identify new cellular therapeutic targets.
The research was conducted on normal (control) and keloid human skin samples collected from
consenting patients undergoing keloid removal and skin transplantation surgeries at the Steve
Biko Academic Hospital. The tissue structure of normal/control skin and keloids as well as mast
cell and collagen distribution were evaluated using histological techniques. Transmission
electron microscopy techniques were undertaken in order to investigate morphological and
ultrastructural features of cells of the epidermis and dermis. A further detailed analysis of the
ultrastructure of keloid fibroblasts and mast cells was undertaken. The findings of this study
have lead to a new hypothesis related to keloid formation. Increased fibroblast activity, intracellular collagen production and fibroblast and mast cell
interactions were seen in keloid tissue. Changes in the morphology of keratinocytes and
melanocytes were observed, where the cytoplasmic processes of both cells were shorter and
cells were packed closer together in keloids. Keloid tissue appeared to be in a hyperproliferative
state similar to that of the granulation phase of wound healing. Increased amounts of collagen
were found in the extracellular matrix (ECM) of keloid tissue. This is the first study in which the
abnormal accumulation of insoluble collagen fibrils was observed in the cytoplasm.
Degranulation of mast cells had occurred and these cells were found in close association with
fibroblasts. In some instances phagocytosis of collagen by mast cells was also observed.
These observations have led to the hypothesis that transforming growth factor β (TGF-β)
derived from mast cells, inhibits keratinocyte proliferation and stimulates increased collagen
production through increased expression of lysyl oxidase (LOX) by fibroblasts. Intracellular
insoluble collagen formation then occurs due to the rapid, intracellular removal of the C terminal
pro-peptide sequence by C-proteinase which initiates the cascade of insoluble collagen fibre
formation within the fibroblast. Normally this process occurs only within the ECM in response to
the increasing mass of collagen and in an attempt to establish normal tissue homeostasis the
mast cells engulf the bundles of collagen fibres. Increased stress on the epidermal layer causes
increased keratinocyte proliferation, which results in further growth factor mediated replication of
fibroblasts. This creates an endless cycle of collagen synthesis, mast cell degranulation and
mast cell mediated collagen phagocytosis, physical stress on the epidermal layer and
subsequent growth factor release and fibroblast activation, collagen synthesis and subsequent
crowding of keratinocytes and melanocytes.
In conclusion, this study identified keloid formation as a defect of procollagen synthesis and
processing. Phagocytosis of collagen by mast cells indicates that accumulation of these cells
may be a secondary effect to excessive collagen synthesis. In addition, the release of
interleukins, mediators and growth factors may further stimulate collagen fibril formation with the
imbalance toward increased synthesis. This study also identified and confirmed the findings of
other studies that procollagen C-proteinase is an important therapeutic target. / Dissertation (MSc)--University of Pretoria, 2014. / tm2015 / Anatomy / MSc / Unrestricted
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:up/oai:repository.up.ac.za:2263/45920 |
| Date | January 2014 |
| Creators | Arbi, Sandra |
| Contributors | Bester, Megan J., Taute, Helena |
| Publisher | University of Pretoria |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Rights | © 2015 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
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