Investigating the role of imprinted genes as master regulators of placental hormones using trophoblast stem cells

Chibnall, Alice 2025. Investigating the role of imprinted genes as master regulators of placental hormones using trophoblast stem cells. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The placental programming hypothesis coupled with placental endocrine insufficiency describes the complex mechanisms surrounding placental hormone’s role in preparing the pregnant female for motherhood and complications resulting in maternal mental health issues. This thesis focusses on imprinted genes which regulate placental hormones. In human, PEG3 and PHLDA2 have been associated with varying levels of human placental lactogen hormone, whilst not being directly linked. In mouse, Peg3 and Phlda2 have previously demonstrated the ability to regulate the mouse placentas hormone capacity by acting on the development of the endocrine compartment on the mouse placenta, the junctional zone. This thesis used four genetically modified mouse models to further investigate their regulatory capabilities. These were a loss of imprinting model of Phlda2, knockout models of Peg3 (Peg3KO) and Phlda2 (Phlda2KO) and finally a double knockout (DKO) model of both Peg3 and Phlda2. The latter model was to specifically determine the antagonistic behaviour between Peg3 and Phlda2. To establish if the function of these genes is conserved across species, trophoblast stem cell knockout models were generated for both mouse and human and their endocrine capacity was assessed. Elaborating on previous characterisation of the Phlda2 loss of imprinting model, this thesis documented a reduction in placenta weight, junctional zone area and hormone production which was more acutely presented in female placentas and not male. In the placenta assessment of Peg3 and Phlda2 knockout models, Peg3KO placentas demonstrated a male only reduction in junctional zone size and placental hormone production where Phlda2KO placentas demonstrated an increase in both metrics for both sexes. The assessment of the double knockout model revealed the correction to a wild type phenotype in the junctional zone but not in the labyrinth. Mouse trophoblast stem cell models revealed that Peg3 regulates Phlda2 expression and human trophoblast stem cell assessment discovered long elusive causative evidence that PHLDA2 directly regulates human placental lactogen, with the PHLDA2KO human trophoblast stem cell lines demonstrating an increase in human placental lactogen expression. In summary, this thesis contributed to the knowledge surrounding imprinted genes regulation of placental hormones and emphasised the sexually dimorphic characteristic of this action.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	22 October 2025
Last Modified:	22 Oct 2025 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/181839

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