TCF21 as a potential regulator of fibroblast function and repair in COPD

Pohl, Stephanie 2024. TCF21 as a potential regulator of fibroblast function and repair in COPD. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Summary In my thesis, I investigated the expression, distribution, and subcellular localisation of transcription factor 21 (TCF21) in adult human lungs, focusing on its role in both healthy conditions and in chronic obstructive pulmonary disease (COPD). I identified TCF21 in mesenchymal cells in the alveolar region, particularly near alveolar epithelial progenitor cells, and made a novel discovery of its presence in the nucleoli of lung fibroblasts. My findings included TCF21's upregulation in COPD I fibroblasts, indicating its involvement in disease adaptation. Additionally, my investigation into TCF21's molecular roles in primary adult human lung fibroblasts indicated its role as a repressor of cytoplasmic translation events, control of the cell cycle, and apoptosis regulation. RNA sequencing after TCF21 knockdown revealed a distinct ribosomal signature, supporting my initial findings on its localization. This in vitro study also showed that lowering TCF21 levels in primary adult human lung fibroblasts led to cell cycle disruptions and reduced proliferation, indicating TCF21's involvement in these processes. Interestingly, the proliferation of COPD I fibroblasts, marked by significantly increased TCF21 expression, was unaffected following TCF21 knockdown, suggesting an early disease coping mechanism. Finally, I investigated how TCF21 affects the transition of fibroblasts into myofibroblasts, identifying its intricate relationship with TGFβ signalling. My findings revealed that reducing TCF21 levels in primary adult human lung fibroblasts led to an increase in extracellular matrix production and morphological alterations, indicating its importance in ECM remodelling and the differentiation into myofibroblasts. I also discovered that TGFβ suppresses TCF21 expression whilst serum-starvation leads to its upregulation. This suggests that TCF21 may act to moderate the pro-fibrotic effects of TGFβ, highlighting a sophisticated interaction between these elements in the process of lung regeneration that need to be further investigated.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	23 July 2024
Last Modified:	24 Jul 2024 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/170867

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