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Molecular events governing hematopoietic stem cell recruitment in Vivo in murine liver following Ischemia-reperfusion injury

Kavanagh, Dean Philip John (2010)
Ph.D. thesis, University of Birmingham.

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Evidence suggests haematopoietic stem cells (HSCs) can migrate to injured liver and influence tissue repair. However, the molecular adhesive mechanisms governing HSC recruitment to injured hepatic microcirculation are poorly understood. These mechanisms were investigated in vivo following murine hepatic ischemia-reperfusion (IR) injury. HSC adhesion was significantly enhanced in injured livers and could be reduced by blocking CD49d on HSCs or VCAM-1 in vivo. Blockade of HSC CD18, CD31 or CD44 did not alter adhesion. HSC adhesion in sham treated CD31-/- animals was raised compared to wild-type animals and IR injury did not further raise this adhesion. Studies in vitro demonstrated that HSC treatment with inflammatory cytokines or conditioned media/plasma did not upregulate adhesion molecule expression but CXCL12 and CXCL1 did significantly enhance HSC adhesion to endothelium. However, blockade of CXCR4 (CXCL12 receptor) failed to reduce HSC adhesion in vivo following IR injury. Furthermore, we demonstrated exogenous HSCs were identified primarily in the pulmonary circulation and intraportal injection raised recruitment within the liver irrespective of the presence of injury. This study provides novel evidence for the importance of the VLA-4/VCAM-1 pathway in HSC recruitment to IR injured liver, a pathway that may be manipulated in order to enhance hepatic engraftment of these cells clinically.

Type of Work:Ph.D. thesis.
Supervisor(s):Kalia, Neena (Dr)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Cardiovascular Sciences
Subjects:RB Pathology
Institution:University of Birmingham
ID Code:363
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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