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The impact of premature, chronological and in vitro ageing on human smooth muscle cells from different vascular sources

Hussain, Alisah
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Riches-Suman, Kirsten
Thornton, M. Julie
Keywords
Smooth muscle cells, Ageing, Vascular, Premature ageing, Microvessels, Macrovessels, Type 2 diabetes, Subdermal plexus, Skin biology
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The University of Bradford theses are licenced under a Creative Commons Licence.
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Accepted for publication
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University of Bradford
Department
School of Chemistry and Biosciences. Faculty of Life Sciences
Awarded
2024
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PhD Thesis
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Abstract
Ageing can have a significant impact on smooth muscle cell (SMC) function. However, studying age-related changes is difficult due to the inability to investigate SMC biology in-situ longitudinally. Therefore, to mimic the ageing process, in vitro assays can be utilised which are then extrapolated to young vs old ex vivo studies. This work investigates the impact of three models of ageing; chronological ageing, premature ageing and in vitro ageing on SMC phenotype. It aims to characterise the cellular and molecular regulation of all three models in saphenous vein smooth muscle cells (SV-SMC) followed by establishing a protocol for isolating dermal vessel smooth muscle cells (DV-SMC) and to examine phenotypical similarities to SV-SMC. In this present work, SV-SMC were successfully isolated, cultured and characterised to determine cellular phenotype. Bioinformatics and functional clustering analysis enabled miRnome analysis which revealed an upregulation of miRNAs in each model of ageing; miR-17 and miR-130b in premature ageing, miR-31 in chronological ageing and miR-29b2 in in-vitro ageing. These findings were validated using miRNA qPCR. To establish whether the same phenotype was also present in more accessible tissue types, SMC from the sub-dermal plexus were assessed. The gross structures in multiple layers of the skin were compared between young healthy donors and donors undergoing premature ageing, followed by blood vessel quantification which revealed no significant differences. Type 2 Diabetes Mellitus (T2DM) was a model system for premature ageing in this work. .DV-SMC were isolated and characterised for the first time, with similarities to SV-SMC including a trend in the upregulation of miR-17, miR-31, miR29b2 and miR-130b in T2DM DVSMC. Furthermore, morphological and DNA damage studies revealed a trend towards an increase in multinucleation, abberant nuclei and γH2AX positive nuclei in T2DM DV-SMC similar to findings established within T2DM SV-SMC. Ultimately, these data could inform personalised medicine approaches and may enable strategies for identification and treatment of microvascular and macrovascular dysfunction.
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https://bradscholars.brad.ac.uk/handle/10454/20876
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Thesis
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PhD
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