Manshaei, Saba;
(2023)
Investigating the paracrine role of pituitary stem cells in development and the role of their senescent state in pituitary tumourigenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The pituitary gland is the critical regulator of the endocrine system. In mouse models, it has been shown that after the expression of oncogenic mutations in β-catenin, pituitary stem cells enter senescence and activate a pro-inflammatory senescence-associated secretome (SASP). These senescent cells play an important role in the tumourigenesis process. Cellular senescence has also been associated with adamantinomatous craniopharyngioma (ACP), a paediatric pituitary tumour. This project aimed to determine the role of senescent cells and SASP factors in ACP. A mouse model expressing a constitutively active negative regulator of cytokines, BRF1, was crossed with ACP mouse models to determine the role of SASP factors in tumourigenesis. Mice with decreased SASP secretions had reduced tumourigenesis and increased survival. Furthermore, a novel transgenic model (P21FDR/+) was designed and generated to visualise, trace and ablate p21+ senescent cells. This model can be used to examine the role of senescence in ACP tumourigenesis. Investigations of pituitary development revealed that BRF1 is endogenously expressed in SOX2 stem cells. Embryonic expression of constitutively active BRF1 in the pituitary caused severe hypopituitarism due to a lack of terminal differentiation of hormone-producing cells. Hormone production and differentiation were rescued in-vitro and in-vivo by WT pituitary cells, suggesting an underlying paracrine mechanism. Transcriptomics analyses revealed specific ligands secreted by SOX2+ cells, the addition of which to the non-functioning pituitary cells in-vitro also rescued hormone production in non-functioning cells. Together, research during this PhD has highlighted the detrimental role of SASP factors in ACP tumourigenesis, as well as providing evidence for a novel paracrine mechanism by SOX2 stem cells in pituitary development.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the paracrine role of pituitary stem cells in development and the role of their senescent state in pituitary tumourigenesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167250 |
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