title: Adipose derived stromal vascular fraction: therapeutic potential of renal artery administration in renal ischaemia reperfusion injury
Creators: name: Ghita, Ryan
Publisher: name: University of Glasgow
Year: 2021

description: Shortages of kidneys for transplantation is a universal concern. Countries like the United Kingdom have had success improving the number of kidneys available notably through expanding their living donation program. However, trends indicate the discrepancy between supply and demand will never fully be met with current practise. Bioengineering of donor specific organs may provide the ultimate answer, but despite rapidly growing progress it will be many more years until complex organs, such as a kidney, are available for transplantation. Utilising kidneys that traditionally would not be considered suitable for transplantation will drastically increase the donor pool of kidneys. To implant these ‘marginal’ kidneys we have to minimise the ischaemia reperfusion injury (IRI) they sustain during the transplantation process. Cellular therapies offer the greatest potential in ameliorating transplant related IRI and allowing these marginal kidneys to recover with acceptable long-term function. The field of cellular therapies, in particular stem cell therapy, has expanded rapidly in the last ten years. Adipose tissue offers one of the most attractive sources of stem cells due to its relatively easy accessibility and high abundance of stem cells. The adipose derived stromal vascular fraction (ADSVF), which contains the adipose derived stem cells, can quickly be extracted from the adipose tissue with minimal technical expertise. Multiple animal studies of renal IRI have demonstrated significantly improved kidney function after treatment with ADSVF. However, administration of freshly isolated, uncultured ADSVF administered via the renal at the time of transplantation has never been attempted in human kidneys. Before considering clinical translation, we need to better understand the use of ADSVF in such settings. In chapter one, experiments characterise the ADSVF obtained from inguinal and peri-renal adipose tissue of both rats and humans. Chapter two describes the development of a novel animal model which closely mimics the transplant recipient in order to accurately investigate the ADSVF. Chapter three demonstrates the biodistribution of the ADSVF administered via the renal artery and chapter four highlights some of the potential mechanisms of action of the ADSVF. In summary, ADSVF from peri-renal and inguinal adipose tissue consist of a similar heterogenous cell population, although they differ in the proportions of each subset. When administered via the renal artery, ADSVF likely ameliorate IRI via multiple mechanisms, by reducing the immediate injury, modulating the inflammatory response and reducing the progression to fibrosis. Administration via the renal artery is an effective means of reducing non-target biodistribution and deliver the majority of the ADSVF to the cortex of the kidney. The animal model developed as part of this research better mimics the transplant patient, compared to existing models, without increasing the risks to the animal. The findings of this research combined with recently published data using mesenchymal stem cells in human kidney IRI, provides enough support to consider renal artery administration of uncultured ADSVF. Initially this translational research could be performed on declined kidney grafts.