Optimising stem cell therapy for liver disease through modulation of sphingosine 1-phosphate signalling

King, Andrew Laurence (2014). Optimising stem cell therapy for liver disease through modulation of sphingosine 1-phosphate signalling. University of Birmingham. Ph.D.

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Abstract

Liver Disease is a rapidly rising cause of mortality and morbidity in the United Kingdom. A potential role of bone marrow stem cells as a novel therapy for liver disease has been proposed although understanding of the mechanisms involved in mediating both the anti-fibrotic effect and the trafficking of cells to the liver are limited. In this thesis I have investigated the beneficial effect of a purified population of haematopoietic stem cells(HSC) in liver injury and studied mechanisms by which their effect may be optimised. Firstly I confirmed the increased mobilisation and recruitment of HSC to the injured liver and demonstrated a significant anti fibrotic effect of repeated injections of HSC in a murine model of liver injury. Observations from these studies suggested that stimulation of endogenous repair is the mechanism responsible. Sphingosine 1-phosphate (S1P) has been shown to mediate egress of HSC from peripheral tissue into draining lymphatics, I have shown increased levels of S1P in both the blood and liver during liver injury, mediated by upregulation of sphingosine kinase 1. The S1P receptor modulator FTY720 increased the hepatic accumulation of HSC during liver injury without altering HSC recruitment to the liver, suggesting reduced egress of HSC. Ultimately I demonstrated that administration of FTY720 increased the hepatic retention of injected HSC which was associated with an enhanced anti fibrotic action. These studies provide encouraging evidence for the use of HSC in clinical studies and propose a mechanism by which the effect of this rare population of cells may be optimised.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):