Makwana, Komal (2021) Characterisation of endometrial gland defects associated with recurrent missed miscarriage. PhD thesis, University of Warwick.

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Abstract

Recurrent pregnancy loss, defined as multiple miscarriages, is a distressing condition associated with significant physical trauma and psychological morbidity. Miscarriage often causes bleeding in early gestation, reflecting the breakdown of the emerging maternal-fetal interface. However, bleeding is not a prominent feature in missed miscarriage, which typically involves very early-onset fetal growth restriction, fetal bradycardia and ultimately fetal demise. I hypothesised that recurrent missed miscarriage (RMM), defined here as 3 or more ‘silent’ miscarriages, reflects an endometrial glandular defect that compromises histotrophic nutrition before the onset of placental perfusion around 12 weeks of pregnancy. To test this hypothesis, RNA-sequencing data of laser-captured mid-luteal endometrial glands from RMM patients and control subjects were subjected to metabolic modelling using flux variability and balance analysis. Computational modelling revealed a notable metabolic signature in RMM, characterised by heightened oxidative phosphorylation and fatty acid oxidation and decreased glycolysis, which was not attributable to glandular asynchrony. To explore the drivers of this endometrial defect in RMM, I optimised a robust organoid protocol to assess glandular differentiation in vitro. RMM organoids not only recapitulated the in vivo metabolic signature but displayed a multitude of defects caused by more naïve progenitor cells, including attenuated Wnt and Notch signalling, and impaired specification of epithelial cells into differentiated and senescent subpopulations upon progesterone-induced cell cycle arrest and differentiation. Importantly, senescent epithelial cells, which are a major source of growth factors and extracellular matrix proteinases, may critically regulate endoglandular trophoblast invasion and access to glandular secretions in early gestation. Quantification of p16INK4 immuno reactivity in 48 biopsies confirmed that RMM is associated with lack of glandular senescence during the peri-implantation window. Collectively, the data indicate that aberrant metabolic programming of endometrial epithelial progenitor cells compromises glandular function, thus revealing a novel therapeutic target for RMM prevention.

Item Type:	Thesis (PhD)
Subjects:	R Medicine > RG Gynecology and obstetrics
Library of Congress Subject Headings (LCSH):	Miscarriage -- Research, Pregnancy -- Complications, Endometrium, Luteal phase
Official Date:	August 2021
Dates:	Date Event August 2021 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Brosens, Jan J. ; Lucas, Emma ; Christian, Mark (Associate professor)
Format of File:	pdf
Extent:	various pagings : illustrations
Language:	eng

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