Evaluating smooth muscle cell identity and differentiation states in an induced pluripotent stem cell model of pulmonary arterial hypertension

Fendley, Jack (2024) Evaluating smooth muscle cell identity and differentiation states in an induced pluripotent stem cell model of pulmonary arterial hypertension. Masters thesis, University of East Anglia.

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Abstract

Pulmonary arterial hypertension (PAH) is a rare vascular disease characterised by extensive vascular remodelling of the pulmonary arterial microvessel network. One of the main causes of inherited/ familial PAH are mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, however, the penetrance of the mutation in patients is relatively low. Clinical research is focused on elucidating the interdependent and dependent pathways which in a combinatorial manner, contribute to the pathogenesis of this disease. Previously, significant practical limitations have impeded this research, due to animal models not correctly recapitulating all aspects of the disease pathology as observed in humans. Additionally, poor tissue sample quality, which could only be obtained from endstage disease patients, has impeded the ability to research initial triggers and progression events of the disease. In this thesis, the first documented induced pluripotent stem cell (iPSC) derived smooth muscle cell (iPSC-SMC) model of PAH previously described in Kiskin et al., 2018, was used to elucidate the cell identity and differentiation states of iPSCSMCs in vitro. In this thesis, I showed that reduction in BMPR2 either due to genetic mutation or by extrinsic factor TNFα promotes dedifferentiation of iPSC-SMCs in culture, confirmed by immunocytochemistry as well as RNAseq bioinformatics analysis. Additionally, I showed that modulation of BMPR2 and Wnt signalling during SMC differentiation significantly altered SMC differentiation state, which had not been previously described in the literature. Altogether, my work suggests that in addition to the current understanding that PAH is an acquired disorder in part due to inflammatory signalling, PAH could also be a developmental disorder, providing a new explanation for early onset PAH in paediatric cases.

Item Type:	Thesis (Masters)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Jennifer Whitaker
Date Deposited:	04 Apr 2025 11:39
Last Modified:	04 Apr 2025 11:39
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98936
DOI:

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