Haematopoietic stem cell recruitment to injured murine liver sinusoids depends on (alpha)4(beta)1 integrin/VCAM-1 interactions.
OBJECTIVE
Evidence suggests haematopoietic stem cells (HSCs) can migrate to injured liver and influence tissue repair. However, mechanisms governing HSC recruitment to injured hepatic microcirculation are poorly understood. These were investigated in vivo following hepatic ischaemia-reperfusion (IR) injury and in vitro using flow-based adhesion assays.


METHODS
Partial IR was induced in anaesthetised WT or PECAM-1(-/-) mice for 90 min. Recruitment of systemically administered HSCs was monitored and effects of function blocking antibodies against alpha(4)beta(1) integrin, CD18, CD44, PECAM-1 or VCAM-1 investigated. The kinetics and molecular events governing adhesion to murine cardiac endothelial cells in vitro were also determined. Effects of conditioned media from IR injured liver on HSC adhesion molecule expression was determined by FACS.


RESULTS
Administered HSCs homed predominantly to lungs rather than liver, highlighting a potential therapeutic hurdle. Hepatic HSC recruitment following IR injury was inhibited by anti-alpha(4)beta(1) and anti-VCAM-1 antibodies. A role for alpha(4)beta(1) was also confirmed using flow-based adhesion assays. Incubating HSCs with conditioned media from IR injured liver increased alpha(4)beta(1) expression. CD18, CD44 and PECAM-1 were not involved in recruitment.


CONCLUSIONS
This novel study demonstrates that the alpha(4)beta(1)/VCAM-1 pathway mediates HSC recruitment to injured liver. Manipulating this pathway may enhance delivery of HSCs to the liver.
Kavanagh
D P J
DP
Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK.
Durant
L E
LE
Crosby
H A
HA
Lalor
P F
PF
Frampton
J
J
Adams
D H
DH
Kalia
N
N
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D039041:Integrin alpha4beta1 / Q000378:metabolism* / Q000502:physiology; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism* / Q000502:physiology
D017077:Culture Media, Conditioned; D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; D000410:Alanine Transaminase