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Title: Pharmacological mobilisation of murine mesenchymal stem/progenitor cells : identifying potential mechanisms
Author: Redpath, Andia Nicole
ISNI:       0000 0004 6423 1131
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Mesenchymal stem/progenitor cells (MSPCs) isolated from adult tissues and expanded ex vivo exhibit multipotency, immunomodulatory and regenerative properties; and thus are currently being assessed in many clinical trials. In contrast, this study focuses on understanding native MSPC properties to ultimately exploit their regenerative potential using pharmacological methods. It was previously demonstrated that pretreatment of mice with VEGF over 4 days primed MSPCs for mobilisation from the bone marrow (BM) to the peripheral blood in response to the CXCR4 antagonist, AMD3100. In this study, possible mechanisms underlying this response were investigated. In order to examine the effect of VEGF on MSPCs an in vitro system was initially established. Furthermore, an in vivo approach was utilised to investigate the mechanism whereby mobilising factors prime MSPCs for mobilisation by AMD3100. Mesenchymal and haematopoietic stem/progenitor cell (HSPC) mobilisation were compared to give insight into whether common or distinct pathways are involved. Stem cells are actively retained in the BM due to their expression of CXCR4 and the constitutive expression of CXCL12. It was demonstrated in this study that AMD3100 stimulates HSPC and MSPC mobilisation by reversing the gradient of CXCL12, from the BM to the blood; an effect that could be blocked with a novel CXCL12 neutraligand. MSPCs in the BM are closely associated to tissue-resident macrophages, and through their interaction regulate retention of HSPCs. In this study, macrophage depletion induced mobilisation of HSPCs and significantly enhanced their mobilisation by AMD3100. In contrast, mobilisation of MSPCs was impaired; suggesting that mobilising factors may signal via macrophages to prime MSPCs. Similarly, mice pretreated with G-CSF – shown to also deplete macrophages – impaired pharmacological mobilisation of MSPCs. These results suggest that macrophages play opposing roles in regulating the mobilisation of HSPCs and MSPCs.
Supervisor: Rankin, Sara M. Sponsor: National Heart & Lung Institute ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral