Abeygunawardena, Dhanushi (2018) Understanding cell fate and function decisions of cardiac mesenchymal stem cells. PhD thesis, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW.
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2018 Dhanushi Abeygunawardena_PhD Thesis.pdf Download (121MB) | Preview |
Abstract
The adult heart, albeit the presence of multiple progenitor cell types, is one of the poorly regenerated organsfollowing injury. Extensive characterisation of such progenitor populations is therefore crucial to understanding thepotential of the cells to be manipulated leading to better injury resolution and repair. Cardiac colony forming unitfibroblasts (cCFU-Fs) are a resident progenitor cell population, analogous to bone marrow CFU-Fs, giving rise tocardiac mesenchymal stromal cells (cMSCs) in vitro. While being one of the better characterised progenitorpopulations, intrinsic cell fate decisions driving cCFU-F function in homeostasis and repair are yet to be elucidated.Hence, the aim of this thesis was to initiate understanding the underlying molecular mechanisms that guide cCFU-Fand cMSC outcomes. This aim was addressed using three different approaches; (1) by determining the intrinsiclineage commitment of cMSCs using an unbiased in vitro assay, (2) by investigating the role of the cardiogenictranscription factor T-box 20 (TBX20) which is highly expressed in cMSCs and (3) by comparing the cMSCs fromatria and ventricles to determine the effect of anatomical location within the heart. Serum reduction in growth mediawas used as a method to induce unbiased differentiation of cells in vitro. The assay however, did not behave asanticipated to differentiate the cells. Instead, under low serum conditions, cells lost mesenchymal characteristics andacquired a gene signature similar to that of an active epicardium. Transcriptome analysis confirmed the loss ofmesenchymal character possibly via downregulation of TGFβ signalling and revealed predominantly the paracrinepotential of cMSCs. Deletion of Tbx20 in cCFU-Fs affected clonogenicity of cells while preliminary observationssuggested a role in regulating cMSC differentiation. Comparison of atrial and ventricular cCFU-Fs revealedenrichment of cCFU-Fs in the atria which also showed a higher growth rate in vitro. Relative hypoxia inducedmetabolic changes may have partly contributed to these differences. Additionally, we describe a mouse model tostudy atrial fibrosis which may also provide a platform to characterise reparative and reactive fibrosis. In summary,this thesis presents the developments made in understanding cell fate and function decisions of cCFU-Fs/cMSCsand potential governing factors.
| Item Type: | Thesis (PhD ) |
|---|---|
| Additional Information: | SUPERVISORS: Harvey, Richard, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW. Wilkins, Marc, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW. Forte, Elvira, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW. THESIS EMBARGO: 2020 |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Jan 2019 04:12 |
| Last Modified: | 16 Oct 2020 01:07 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/791 |
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