Investigating the effects of stem cell therapies in experimental models of renal ischemia-reperfusion injury

[摘要] The incidence of end-stage renal disease is increasing in Western Society.Renal transplantation is known to be the optimal treatment for ESRD, being associated with significant reduction in morbidity, mortality for patients and cost for wider society when compared to remaining on dialysis.Unfortunately, the growing number of patients listed for renal transplantation has occurred without a matched supply in the number of suitable organs.This has led to longer average waiting times for increased numbers of patients, who consequently suffer adverse outcomes at considerable cost to the National Health Service as a result of organ shortage.One strategy employed by clinicians to meet demand for organs has been to transplant ‘suboptimal’ kidneys’ historically rejected as unsuitable for transplantation, which are usually retrieved from older and less fit donors.Sometimes referred to as ‘extended criteria’ or ‘marginal kidneys’, such allografts are more prone to damage in the peri-transplantation period, with the major pathological process recognised to be ischemia-reperfusion injury (IRI).Although functioning ‘marginal’ allografts have been shown to confer benefit to recipients, early transplant failure is associated with negative outcomes.Consequently, there is a real need to develop treatments to mitigate renal IRI, especially since the use of ‘marginal’ kidneys is likely to increase. Stem cell therapy has been shown to protect solid organs from IRI in a number of different animal models.Consequently, there is great interest in researching the ability of stem cell-based therapies to ameliorate solid organ damage and perhaps to encourage organ regeneration.However, debate exists regarding the exact mechanism by which stem cells produce their effects.Some researchers suggest that stem cells directly differentiate to replace specialised cell types in damage organs.Other investigators conclude that stem cells produce their effects in a paracrine fashion via the release of extracellular vesicles with the horizontal transfer of genetic material between cells. Unfortunately, no therapies are currently in widespread use to reduce damage to allografts in the peri-transplant period.In part, this reflects the lack of robust small animal models for screening potential renal IRI therapies before testing in large animal models.Furthermore, clinical application has been limited by safety concerns, and particularly by the risk of stem cells undergoing malignant transformation and subsequent tumour formation in recipients.However, investigators hypothesise that the use of stem cell-derived, extracellular vesicles may confer similar beneficial therapeutic efficacy, but lack many of the side effects associated with stem cells themselves.This thesis describes experiments in which stem cell-based therapies are tested in conventional and novel animal models of renal IRI and renal transplantation. In Chapter 3, initial experiments unexpectedly demonstrated the potential of ex vivo expanded stem cells to undergo malignant change and induce tumour formation in recipient animals.Therefore, the subsequent research investigated the effects of freshly isolated stem cells or those of novel extracellular vesicle preparations.In Chapter 4, experiments unexpectedly demonstrated the shortcomings of a conventional rat model of renal IRI.Therefore, Chapter 5 describes the development of a novel rat of model of renal IRI, in which stem cell-based therapies may be tested. Using this animal model, Chapters 6 and Chapter 7 describe the investigation of novel stem cell-based therapies and their effects on renal IRI.Some of these treatments were found to protect kidneys from IRI damage with preservation of renal function and structure in the medium to long-term.Chapter 8 describes a rat model of renal transplantation, in which therapies were investigated after being screened for efficacy in the novel rat IRI model.Although no functional difference was demonstrated, renal histology was preserved by treatment, although the mechanisms by which this effect occurred remain unclear.These findings suggest that stem cells and their extracellular vesicles have the potential to reduce peri-transplantation renal IRI and hence improve long-term outcomes of ‘marginal’ allografts.However, clinical translation requires the long-term efficacy and safety of these novel therapies to be investigated in large animal models of renal transplantation, before further testing in pilot studies.

[发布机构] University:University of Glasgow;Department:Institute of Cardiovascular and Medical Sciences

[关键词] Renal ischemia, stem cells, animal models.