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 ischemia-reperfusion (IR) injury and in vitro using flow-based adhesion assays.
Design: Partial IR was induced in anaesthetised WT or PECAM-1-/- mice for 90 minutes. Recruitment of systemically administered HSCs was monitored and effects of function blocking antibodies against α4β1 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-α4β1 and anti-VCAM-1 antibodies. A role for α4β1 was also confirmed using flow-based adhesion assays. Incubating HSCs with conditioned media from IR injured liver increased α4β1 expression. CD18, CD44 and PECAM-1 were not involved in recruitment.
Conclusions: This novel study demonstrates that α4β1/VCAM-1 pathway mediates HSC recruitment to injured liver. Manipulating this pathway may enhance delivery of HSCs to the liver.