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


METHODS
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.


RESULTS
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.
Crosby
Heather A
HA
Centre for Liver Research and NIHR Biomedical Research Unit for Liver Disease, University of Birmingham and Queen Elizabeth Hospital Birmingham, Birmingham B15 2TT, UK. h.a.crosby@bham.ac.uk
Lalor
Patricia F
PF
Ross
Emma
E
Newsome
Philip N
PN
Adams
David H
DH
D018952:Antigens, CD34 / Q000378:metabolism; D001659:Biliary Tract / Q000166:cytology; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D066298:In Vitro Techniques; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000166:cytology* / Q000276:immunology; D054367:Receptors, CXCR3 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018952:Antigens, CD34; D018821:CD18 Antigens; C497483:CD44 protein, human; C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D016023:Integrins; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1