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Title: Use of mesenchymal stem cells for preconditioning of kidney grafts in an ex-vivo kidney perfusion model
Author: Vallant, Natalie
ISNI:       0000 0004 7963 7337
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Introduction: One of the biggest issues in transplantation today is the lack of suitable transplantable organs for an increasing number of patients on the transplant waiting lists. Efforts to address this problem are made by the including organs from extended-criteria and donation-after-cardiac death donors, however these organs show inferior outcomes. Advances in organ preservation are needed to focus on techniques to assess and optimise organ viability prior to transplantation. Methods: This research focuses on organ preconditioning using hypothermic- and normothermic ex-vivo machine perfusion technology in combination with stem cell treatment. A transplational approach ranging from small animal models via porcine to human models was used with an intent to facilitate translation of findings into clinical practice. A portable rapid sampling micro-dialysis (rsMD) device was tested which might enable live monitoring of kidney grafts during preconditioning periods and help estimate the condition of organs. Results: In the first head to head comparison between hypothermic and normothermic machine perfusion for organ preconditioning ex-vivo, an advantage for hypothermic perfusion was detected in the porcine model. Contrary to this, in the transplational model using human organs, the outcome was dependent on demographic backgrounds of the organs; especially the cold ischemia time organs were exposed to had an impact on which perfusion modality was better for an organ. RsMD can successfully provide detailed real-time information on tissue and organ viability at all timepoints of organ preservation. Delivery of Mesenchymal Stem Cells (MSC) into grafts ex-vivo by machine perfusion was possible for the hypothermic- as well as the normothermic setting. MSCs could be traced within the grafts, but did not immediately alter their function. Conditioned Mesenchymal Stem Cell media can influence the phenotype of immune cells, e.g. macrophages. Dependent on the genetic background of MSCs, the obtained conditioned media showed to influence macrophages in different ways. Conclusion: This research has been successful in its overall objective to introduce Mesenchymal Stem Cells into ex-vivo machine perfusion settings. By doing so the goal would be to alleviate ischemia reperfusion injury of organs for transplantation and to thereby expand the pool of acceptable donor organs.
Supervisor: Papalois, Vassilios ; Pusey, Charles Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral