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Title: Role of mast cells in women's health and disorders of the endometrium
Author: De Leo, Bianca
ISNI:       0000 0004 7229 1505
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2017
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During the normal menstrual cycle, the human endometrium undergoes extensive tissue remodelling under the influence of ovarian-derived hormones. The endometrium has well defined stromal and epithelial compartments with the former containing both a well-developed vasculature as well as a diverse population of immune cells. Mast cells (MCs) are long-lived tissue resident immune cells characterised by the presence of granules containing proteases. Mast cells have been detected in the human uterus but little is known about their regulation or the impact of steroids on their differentiation status. Recently MCs have been implicated as key players in physiological and pathological pain pathways but little is known about their role in endometrial pathologies. Endometriosis is a chronic incurable condition characterized by the presence of endometrial tissue outside the uterine cavity: women with endometriosis can suffer from a debilitating range of symptoms including chronic pain. Whilst the aetiology of endometriosis is uncertain, close proximity between MCs and nerves has implicated them in aberrant activation of pain pathways. The aims of the current project were: 1. To determine the spatial and temporal location of uterine MCs and to explore their phenotype including expression of steroid receptors. 2. To explore the activation status of MCs in women with endometriosis and/or pain, 3. To explore the use of cells and mice as models to investigate the phenotype of mast cells and their regulation by steroids. Mast cell proteases tryptase and chymase were detected by RTPCR and immunohistochemistry in “full thickness” (uterine lumen to endometrial-myometrial junction) biopsies from women undergoing hysterectomy. In agreement with previous findings MCs were most abundant in the myometrium. Uterine MCs were predominantly of the classical MC subtypes: tryptasepos/chymaseneg and tryptasepos/chymasepos but a rare third subtype was also identified as tryptaseneg/chymasepos. Mast cell activation/degranulation was cycle stage dependent and for the first time their steroid receptor phenotype was identified as ERαneg/ERβpos/GRpos, suggesting potential regulation by the uterine steroid microenvironment. Studies on tissue samples from women with endometriosis revealed MCs with an altered activation status in the pelvic peritoneal wall, compared to controls, which showed an intense diffuse immunoexpression of chymase suggestive of MC activation and release of this protease during normal physiology of the peritoneum. Surprisingly, analysis of peritoneal fluids from controls, women with pain but no endometriosis, and pain with endometriosis did not detect differences in numbers of MCs or concentrations of tryptase or chymase. Analysis of peritoneal biopsies also provided the first evidence for a striking increase in immunoexpression of PAR-2, a protease-activated receptor, in women suffering from chronic pelvic pain and/or endometriosis which may provide a mechanism by which mast cell derived factors may alter pain pathways. Studies in a mouse model of endometriosis identified MCs within endometria-llike lesions and offer a platform for future studies. In vitro explorations using MCs derived from peripheral blood precursors and HMC-1, a cell line derived from a patient with MC leukaemia confirmed expression of ERβ but did not support previous studies claiming cells were ERαpos. In summary, this study has provided novel insights into the phenotype of endometrial mast cells in the normal cycling endometrium and contrasted them with those in women with endometriosis and pelvic pain. This is the first study to identify MCs as ERβpos. Further studies are required to determine whether inhibition of PAR- 2 might offer a therapeutic target in women with chronic pelvic pain.
Supervisor: Saunders, Philippa ; Critchley, Hilary Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: mast cells ; endometriosis ; tryptase ; chymase ; PAR-2