Dr Sarah Herrick (BSc, PhD) - research
The overall goal of our studies is to understand the fundamental cellular and molecular mechanisms involved in normal turnover of extracellular matrix molecules during tissue repair, the way these processes are altered leading to excessive healing (scarring/fibrosis) or delayed healing (chronic wounds) and to identify ways of regulating these processes therapeutically. We are using a number of experimental systems including cell culture assays, in vivo animal models and human biopsy tissue analysis, as well as a range of cellular, histological, molecular and biochemical techniques to elucidate mechanisms regulating these tissue repair disorders.
Peritoneal repair and adhesion formation
An extremely common problem of surgery in the abdomen is peritoneal adhesion formation where organs, which should normally be separate, become joined by fibrous bands of tissue. Peritoneal adhesions can cause major complications such as intestinal obstruction, chronic pelvic pain and infertility in women. However, little is known about how adhesions form, how they mature and how they are broken down naturally in the body. Our previous histological and ultrastructural studies have shown that adhesions were well vascularised and surprisingly well innervated. We also found that the omentum or "policeman of the abdomen" was more often that not involved in adhesion development. Our current studies are aimed at understanding the role of the initial wound matrix, deposited as a fibrin-rich clot between injured surfaces, and the fibrinolytic proteases involved in its breakdown. We have shown that this provisional fibrin matrix plays a major role in regulating collagen production both in tissue culture assay systems and in vivo models. Furthermore, our recent studies suggest that a defect in fibrin removal results in an even greater accumulation of collagen which we think leads to subsequent fibrosis and adhesion formation.
Stem cells in the peritoneal cavity
The mesothelium consists of a single layer of flattened mesothelial cells that lines the peritoneum and the majority of internal organs, playing important roles in maintaining normal serosal integrity and function. A mesothelial `stem' cell has not been identified, but evidence from numerous studies suggests that a `progenitor' mesothelial cell exists. Although mesothelial cells are of a mesodermal origin, they express characteristics of both epithelial and mesenchymal phenotypes. In addition, following injury, new mesothelium regenerates via centripetal ingrowth of cells from the wound edge and from a free-floating population of cells present in the peritoneal fluid, the origin of which is currently unknown. Recent findings have shown that mesothelial cells can undergo an epithelial to mesenchymal transition, and transform into myofibroblasts and possibly smooth muscle cells, suggesting plasticity in nature. Evidence suggests that mesothelial cell progenitors are able to switch between different cell phenotypes depending on their local environment and state of activation. Our present studies are focused on a detailed investigation, involving selective cell isolation together with cell labelling and tracking studies, to determine the true existence of a mesothelial "stem" cell. It is anticipated that our findings will lead to a better understanding of the role of these progenitor cells in the development of pathological processes such as endometriosis and post-operative adhesion formation.
Skin fibrosis and chronic leg ulcers
Another area of interest is the formation of chronic venous leg ulcers, which affect up to 1% of the population in the UK and cause a major drain on Health Service resources. A problem in the circulation of venous blood causes skin of the lower leg to undergo a series of dramatic changes characterized by skin hardening and discolouration, known as lipodermatosclerosis. Over time this region of skin breaks down to form a non-healing ulcer. We are interested in understanding the key events that regulate these initial skin changes and the main factors that cause the skin to breakdown. With clinical colleagues, we have collected skin biopsies from people with venous insufficiency and shown that the pre-ulcerated skin is extremely fibrotic and contains a high level of iron due to leakage of red blood cells. Current studies are assessing whether these features are related or occur independently and if we manipulate them, we can prevent ulcers forming.
Improved tissue-engineered skin replacements
One way of treating chronic non-healing wounds as well as other wound healing defects such as burns is by covering them with a skin graft. These grafts may be from the patient's own skin or engineered artificially. Most tissue-engineered skin replacements consist of a dermal and a surface epidermal layer but lack a lower subcutaneous fat component. Problems can occur if the graft is rejected due to poor vascularisation or if over time, scarring develops leading to loss of tissue function. Little work has been done to study the interaction of cells in the different skin layers, in particular, the role of the subcutaneous cells in directing the growth of vascular and neural networks and preventing excess scarring. Our overall aim is to generate the next generation of skin replacements that have improved graft take and better integration with host tissue. This work is being carried out in collaboration with the UK Centre for Tissue Engineering, directed by Professor Tim Hardingham.
Herrick S, Blanc-Brude, Gray A, Laurent G. (1999). Molecules in Focus: Fibrinogen. Int J Biochem Cell Biol 31, 741-746.
Shah M, Revis D, Herrick S, Baille R, Thorgeirson S, Ferguson M, Roberts A. (1999). Role of elevated plasma transforming growth factor-β1 levels in wound healing. Am J Pathol 154, 1115-1124.
Herrick S, Mutsaers S, Ozua P, Sulaiman H, Omer A, Boulos P, Foster M, Laurent G. (2000). Human peritoneal adhesions are highly cellular, innervated and vascularised. J Pathol 192, 67-72.
Sulaiman H, Gabella G, Davis C, Mutsaers S, Boulos P, Laurent G, Herrick S. (2000). Growth of nerve fibres into murine peritoneal adhesions and their possible significance in pelvic pain. J Pathol 192, 396-403.
Sulaiman H, Gabella G, Davies C, Mutsaers S, Boulos P, Laurent G, Herrick S. (2001). Presence and distribution of sensory nerve fibres in human peritoneal adhesions. Ann Surg 234, 256-261.
Foley-Comer AJ, Herrick SE, Al-Mishlab T, Prele CM, Laurent GJ, Mutsaers SE. (2002) Serosal repair involves incorporation of free-floating mesothelial cells. J Cell Sci 115: 1383-1389.
Sulaiman H, Dawson L, Laurent GJ, Bellingan GJ, Herrick SE. (2002). The role of plasminogen activators in peritoneal adhesion formation. Biochem Soc Trans 30, 126-131