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