- Title
- Endometrial stem/progenitor cells in endometrial regeneration, carcinogenesis and aging
- Creator
- Syed, Shafiq Mukhtar
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Uterus is one of the most regenerative organs of human body, and, is regulated by ovarian sex hormones. Throughout the reproductive life it undergoes >400 cycles of degeneration and regeneration during which endometrium, the inner lining of uterus, regrows completely to a thickness of 4-10mm every month. Such a remarkable regeneration potential can only be explained by the existence of adult stem cells in uterus. Adult stem cells have the potential to contribute to the pool of cancer initiating cells (CICs). Thus, identifying these stem cells and understanding their regulation will provide newer insights into endometrial physiology and disease. However, owing to the lack of uterine stem cell specific markers, there is no definitive evidence for the existence of uterine stem cells. Nearly 85% of endometrial cancers (EC) are estrogen-driven. Once reproductive life is over, and menopause sets in, there is a marked reduction in the circulating levels of ovarian hormones due to decline in the follicular reserves. Interestingly, the risk of EC development increases with age, and is 10 times higher in women aged 50 and above. Therefore, it remains unclear how aging causes EC development despite having diminished ovarian follicular reserves and therefore, the reduced levels of estrogen. Identifying uterine stem cells within their resident niches and the key regulatory pathways involved, and establishing uterine cell lineage hierarchy is crucial to investigate how dysregulation in these pathways lead to the development of EC. It might also provide newer insights into the pathogenesis of endometriosis, particularly in cases where endometrial tissue grows ectopically outside the peritoneal cavity. In this thesis, we have identified uterine stem cells within their resident niches and also define their specific markers. We used a suite of transgenic mouse models to label genetically the uterine epithelial and mesenchymal lineages, and then traced the fate of these labelled cells to identify adult stem cells. We showed that endometrial epithelium self-renews during development, growth and regeneration throughout life. This self-renewal process is fueled by a subset of glandular epithelial cells which are Wnt-responsive and express Axin2. These Axin2+ glandular epithelial cells act as long-lived bi-potent epithelial stem cells that give rise to the both glandular and luminal epithelium. In response to tamoxifen administration, an estrogen agonist and a known inducer of EC, the progenies of these Axin2⁺ cells comprise the majority of the resulting epithelial hyperplastic lesions, the precursor of EC. Thus Axin2⁺ cells are likely the cells of origin for the EC. Furthermore, we show that there is no flux of cells between epithelial and mesenchymal lineages. In fact, all the uterine mesenchymal cells, including stromal fibroblasts and myometrium arise from embryonic Ng2-expressing pericytes, which act as uterine mesenchymal stem cells. These results show that Wnt signaling is responsible for the maintenance of endometrial epithelial stem cells, and, is crucial for endometrial homeostasis and cancer development. We further show that it is the hyperactive Wnt signaling in aged endometrium that is responsible for the development of endometrial hyperplasia, despite the reduction in estrogen levels. This upregulation in Wnt signaling is in turn mediated by age-related changes in endometrial stroma, which results in its altered extracellular matrix (ECM) dynamics and increased stiffness. The transduction of altered ECM compliance by epithelial cells to result in hyperactive Wnt signaling is mediated through integrin-focal adhesion kinase (FAK) signaling. In conclusion, we have defined uterine cell lineage hierarchy and identified epithelial and mesenchymal stem cell specific markers. Furthermore, we identified the role of Wnt signaling in endometrial cancer development in aged women. By studying age-related endometrial stromal changes, we also defined a prognostic stromal cell signature for EC patients.
- Subject
- uterine stem cells; endometrial regeneration; uterine aging; endometrial cancer; Wnt signaling
- Identifier
- http://hdl.handle.net/1959.13/1390990
- Identifier
- uon:33154
- Rights
- Copyright 2018 Shafiq Mukhtar Syed
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 3 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 286 KB | Adobe Acrobat PDF | View Details Download |