Adhesion of human haematopoietic (CD34+) stem cells to human liver compartments is integrin and CD44 dependent and modulated by CXCR3 and CXCR4

Haematopoietic stem cells (HSC) have previously been shown in some studies to migrate to damaged and diseased liver where a small proportion will engraft. Such cells can promote liver repair in rodent models of liver injury and lead to improved liver function in uncontrolled clinical studies. In order to maximize the engraftment of cells for clinical applications it is necessary to understand the molecular mechanisms that regulate stem cell recruitment and retention. Our aim therefore was to determine which factors where involved in adhesion of circulating HSC to liver endothelium and sequestration around epithelial cells within the liver.

Haematopoietic stem cells (HSC) have previously been shown in some studies to migrate to damaged and diseased liver where a small proportion will engraft. Such cells can promote liver repair in rodent models of liver injury and lead to improved liver function in uncontrolled clinical studies. In order to maximize the engraftment of cells for clinical applications it is necessary to understand the molecular mechanisms that regulate stem cell recruitment and retention. Our aim therefore was to determine which factors where involved in adhesion of circulating HSC to liver endothelium and sequestration around epithelial cells within the liver.

CD34(+) populations use alpha4beta1, beta2 integrins and CD44 receptors to bind to the ligands VCAM-1/fibronectin, ICAM-1, and hyaluronic acid expressed on sinusoidal vessels in tissue sections and to primary human HSEC. Binding to BEC was mediated by the interaction of beta1 and beta2 integrins with VCAM-1 and ICAM-1 respectively. A role for chemokines is supported by our finding that pertussis toxin inhibits CD34(+) cell adhesion to BEC and HSEC and by the ability of CD34(+) cells to migrate to CXCR3 and CXCR4 ligands.

We examined the ability of CD34+ populations from peripheral and mobilized blood and the CD34-expressing cell line KG1a to bind to human hepatic sinusoidal endothelial (HSEC) and biliary epithelial cells (BEC) in vitro.

We report that all CD34(+) populations express alpha4beta1, beta2 integrins and CD44. Liver tissue sections and primary liver cells expressed the corresponding ligands VCAM-1/fibronectin, ICAM-1 and CD44. Pertussis toxin was shown to decrease binding of CD34(+) cells and the cells migrated to CXCR3 and CXCR4 ligands. Conclusions: CD34(+) populations use alpha4beta1, beta2 integrins and CD44 receptors to bind to the ligands VCAM-1/fibronectin, ICAM-1, and hyaluronic acid expressed on sinusoidal vessels in tissue sections and to primary human HSEC. Binding to BEC was mediated by the interaction of beta1 and beta2 integrins with VCAM-1 and ICAM-1 respectively. A role for chemokines is supported by our finding that pertussis toxin inhibits CD34(+) cell adhesion to BEC and HSEC and by the ability of CD34(+) cells to migrate to CXCR3 and CXCR4 ligands.