The therapeutic use of mesenchymal stem cells for treating kidney disease
thesisposted on 01.03.2017, 02:06 by Wise, Andrea Frances
A surge in the prevalence of chronic diseases, including chronic kidney disease (CKD), has caused a major shift in the developed world’s disease profile. The increasing incidence of CKD is in part due to the escalating incidence of type 2 diabetes. For end-stage renal disease (ESRD) patients, the only renal replacement therapy options for kidney disease patients are dialysis and kidney transplantation. However, dialysis places a substantial burden on patient quality of life and the global healthcare systems, and there is a shortage of donor organs for transplantation. Together, these issues highlight the urgent need for new therapeutic approaches. The adult kidney has the capacity, although somewhat limited, to undergo regeneration and repair following injury. This process is primarily governed by the surrounding microenvironment, with the nature of the inflammatory response playing a large part in determining disease outcome. Monocytes and macrophages are the principal immune cells that infiltrate the diseased kidney, where signals from the local milieu determine their activation and functional state. Therefore, given a favourable environment, monocytes and macrophages have the ability to resolve inflammation and promote repair, leading to the restoration of renal architecture and function. Mesenchymal stem (stromal) cells (MSCs) possess unique immunomodulatory and cytoprotective properties, making them an ideal candidate for a range of therapeutic applications, including kidney disease. This thesis investigated the reparative potential of MSCs to promote kidney regeneration in ischaemia/reperfusion injury (IR), a model of acute kidney disease, and evaluated the mechanisms involved in the attenuation of structural injury and functional decline of the kidneys. Additionally, the effect MSCs have on the polarisation of murine macrophages and monocytes isolated from type 2 diabetic patients with ESRD were assessed. In Chapter 2, MSCs derived from human bone marrow were characterised and compared to murine bone marrow-derived MSCs. Following administration to mice with IR injury, human MSC treatment promoted structural repair resulting in reduced apoptosis and increased re-epithelisation of the damaged tubular epithelium. In Chapter 3, the renoprotective mechanisms by which the human MSCs promoted repair were examined. It was shown that following administration to mice with IR injury, MSCs homed to the injured kidney where they afforded protection, indicated by reduced blood urea nitrogen, serum creatinine and proximal and urinary kidney injury molecule-1. MSC treatment increased matrix metalloproteinase-9 activity, which coincided with a reduction in collagen accumulation. In vitro, MSCs promoted the polarisation of murine bone marrow-derived macrophages towards a reparative ‘M2’ phenotype, a process mediated by paracrine mechanisms. In Chapter 4, the effects of MSCs on human monocytes isolated from patients with type 2 diabetes and ESRD or control subjects were determined. MSCs were found to retain the ability to alter the gene profile and phenotype of monocytes, even when isolated from this chronic inflammatory environment. Overall, results from this thesis show that MSCs hold great promise as a treatment strategy for kidney disease. Therapeutic manipulation of the kidney microenvironment with MSCs could alter the polarisation of monocytes and macrophages towards a reparative phenotype, halt disease progression and even promote kidney regeneration, providing a potential new treatment option for kidney disease patients.