Martinas, Ioana-Roxana
(2023)
Investigating the role of human umbilical mesenchymal stromal cells as therapies in a model of renal IRI in different mouse strains.
Doctor of Philosophy thesis, University of Liverpool.
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Abstract
Acute kidney injury (AKI), a common complication in hospitalised patients, has been associated with a high mortality rate as well as progression to chronic kidney disease and end-stage renal failure. AKI does not have a distinct pathophysiology as the disease can be brought about by different insults from nephrotoxicity and sepsis to surgical procedures. Regardless of the initial cause, AKI is characterised by a reduction in blood flow to the kidneys and subsequent hypoxia, processes which are associated with inflammation and immune system activation. Macrophages are highly versatile cells of the immune system, ubiquitous in all tissues, and have been identified to play a central role in both the injury phase and the subsequent resolution of inflammation in animal models of kidney disease. Despite recent advances in medical treatment, currently, there is no cure for AKI, and the disease is managed with fluid therapy, dialysis and ultimately, transplantation. Over the last two decades, extensive research done within the fields of regenerative medicine and pre-clinical research has proposed mesenchymal stromal cells (MSCs) as the main therapy for the treatment of various inflammatory diseases, including AKI. MSCs have become an attractive tool for cell-based therapies due to their potent immunosuppressive and immunomodulatory functions with effects on both innate and adaptive immune cells, including monocytes and macrophages. Nevertheless, the precise mode of action of these therapies is still largely unknown. The work in this thesis aimed to characterise and compare the injury response to bilateral renal ischaemia-reperfusion injury (IRI), and on this basis, characterise and compare the regenerative response to cellular therapies following bilateral renal IRI in three different mouse strains. Throughout all the experiments within this thesis I have demonstrated that bilateral renal IRI leads to strain-dependent responses. I have employed a series of experiments that assessed renal function, weight, macrophage levels in kidneys and spleens, and cytokine levels in plasma and kidneys to characterise and compare the effect that bilateral renal IRI has on three different mouse strains – BALB/c, C56BL/6 albino and CD1. Importantly, the application of human umbilical cord (hUC) MSC therapies failed to result in an efficacious response in ameliorating kidney injury, regardless of mouse strain. Despite this observation, I was able to demonstrate that hUC-MSC treatment can marginally modulate macrophages in kidney and spleen, and influence cytokine levels in the kidney. However, these effects were not replicated across the three strains and displayed high inter-strain variability. Further work is required into the mode of action of MSCs so as to better replicate the results seen in pre-clinical studies and to translate these into the clinic.
| Item Type: | Thesis (Doctor of Philosophy) |
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| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 08 Feb 2024 16:54 |
| Last Modified: | 08 Feb 2024 16:55 |
| DOI: | 10.17638/03177018 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177018 |
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