- Title
- The identification of novel paracrine factors expressed by human stem cells of mesenchymal origin to develop regenerative non-cellular therapies for cardiac fibrosis
- Creator
- Mabotuwana, Nishani Sandunika
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Introduction: Stem cells of mesenchymal origin, particularly bone marrow-derived mesenchymal stem cell and cardiac stem cells have been investigated for their potential to promote cardiac repair following ischaemic damage. It has been proposed that these cells may exert their protective effects via paracrine signalling. Aim: To identify and investigate paracrine factors released by stem cells of mesenchymal origin. Methods and Results: To investigate this aim, three studies were conducted: 1) A systematic review which consolidated evidence for the “paracrine hypothesis” in the context of ischemic heart disease. 234 individual protective paracrine factors were identified, including VEGF, HGF, and FGF2. 2) Quantitative proteomic profiling of subcellular compartments of bone marrow derived mesenchymal stem cells and W8B2+ cardiac stem cells resulted in the identification of hundreds of proteins of interest that were upregulated. Particularly, MCAM and SEMA7A were highly expressed in both stem cell populations. RNA sequencing identified that Mcam and Sema7a were abundant in stromal and endothelial cells, with expression decreasing with age. In vitro, MCAM and SEMA7A significantly increased wound closure in coronary artery endothelial cells in a dose dependent manner. 3) Lastly, laminin was investigated for its potential to deliver and promote the benefits of identified factors of interest. Human cardiomyocytes, cardiac fibroblasts, and coronary artery endothelial cells were subjected to hypoxia/ reoxygenation with or without laminin coating to determine effects of laminin on apoptosis, fibrosis, inflammation, hypoxic damage, cell proliferation, and viability under hypoxic conditions. Overall, there was no clear improvement induced by laminin. Conclusions: Together, the data presented in this thesis has resulted in the identification of a wealth of paracrine factors that could serve as therapeutic targets for cardiac repair following ischaemic damage. This wealth of data holds the potential to revolutionise our approach to managing fibrotic disease progression, and therefore improve the overall quality of life patients following a myocardial infarction or heart failure diagnosis.
- Subject
- mesenchymal stem cells; cardiac stem cells; paracrine; myocardial ischaemia; fibrosis; cardiac repair; cardiac regeneration; proteomics
- Identifier
- http://hdl.handle.net/1959.13/1511310
- Identifier
- uon:56483
- Rights
- This thesis is currently under embargo and will be available from 25.02.2025, Copyright 2024 Nishani Sandunika Mabotuwana
- Language
- eng
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