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Impact of the endometrial microenvironments on uterine natural killer cells
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Kong, Chow Seng (2023) Impact of the endometrial microenvironments on uterine natural killer cells. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3956941
Abstract
The loss of a pregnancy is a devastating experience for many couples. Apart from physical trauma, miscarriage is associated with psychological pathology. Each loss also increases the likelihood of obstetrical complications in ongoing future pregnancies, such as pre-term birth and foetal growth restriction, thus compounding the economic burden on healthcare providers and society. Dysregulation of uterine natural killer (uNK) cells is believed to be an important cause of recurrent miscarriage. However, the biological functions and cellular dynamics of uNK cells in cycling endometrium remain poorly characterised, hampering the development of effective strategies for the prediction and prevention of recurrent miscarriage. The aim of my work was to gain insights into pathophysiological roles of uNK cells in the peri-implantation endometrium.
First, I determined if uNK cells play a role in biosensing and selection of human embryos at implantation. I demonstrate that uNK cells highly express CD44, the canonical hyaluronan (HA) receptor. In co-culture experiments, high- but not low-molecular weight HA abolishes uNK cell-mediated killing of stressed/senescent decidual cells, a process essential for successful transformation of the cycling endometrium into the decidua of pregnancy. Importantly, killing of stressed/senescent decidual cells by uNK cells was also inhibited upon exposure to medium conditioned by IVF embryos that failed to implant, but not successful embryos. Inhibition of uNK cell cytotoxicity was caused by lack of embryonic hyaluronidase 2 production, indicating that uNK cells are indirect sensors of embryo fitness and integral to the rapid elimination of a low-fitness conceptus by promoting menstruation-like tissue breakdown. Next, I used multiple approaches, including immunohistochemistry, flow cytometry and single cell RNA-sequencing, to map the uNK cell dynamics. I demonstrate that the implantation window coincides with the transition of cytotoxic KIR-CD39- uNK cells to cytokine producing KIR+CD39- and KIR+CD39+ subsets. Apart from temporal changes, uNK subsets are spatially regulated with cytokine producing uNK cells residing predominantly with subluminal progesterone-resistant stromal cells and their cytotoxic counterparts with underlying progesterone-dependent decidualizing cells.
Further, I identified TAGAP and ITGAD as putative biomarker genes of cytotoxic and cytokine-producing uNK cells, respectively. RT-qPCR analysis of 242 pre-pregnancy biopsies demonstrated that a low ITGAD/TAGAP ratio, normalised for cycle day, is associated with future miscarriages. Finally, building on the in vivo evidence that endometrial stromal cells control differentiation of uNK cells, I combined gene silencing with functional assays in primary co-cultures to demonstrate that recruitment of uNK cells and their subsequent activation and recognition of stressed/senescent cells are controlled by secreted decidual factors, including C-X-C motif chemokine ligand 14, interleukin 15 and TIMP metallopeptidase inhibitor 3.
Taken together, my findings reveal the uNK cells function in close partnership with endometrial stromal cells. During the implantation window, decidualizing stromal cells promote differentiation of uNK cells into functionally distinct subsets, creating a spatial template for interstitial embryo implantation. Screening for imbalance in uNK subsets in pre-pregnancy endometrial biopsy may aid in identifying women at increased risk of miscarriage.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RG Gynecology and obstetrics |
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Library of Congress Subject Headings (LCSH): | Miscarriage, Endometrium -- Physiology, Killer cells, Human embryo -- Transplantation, Pregnancy -- Complications | ||||
Official Date: | February 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Brosens, Jan J. ; Hartshorne, Geraldine M. | ||||
Sponsors: | University of Warwick. Chancellor's International Scholarship | ||||
Format of File: | |||||
Extent: | xiii, 245 pages : illustrations | ||||
Language: | eng |
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