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Haematopoietic stem cell recruitment to injured murine liver sinusoids depends on α4β1 integrin/VCAM-1 interactions
  1. D P J Kavanagh,
  2. L E Durant,
  3. H A Crosby,
  4. P F Lalor,
  5. J Frampton,
  6. D H Adams,
  7. N Kalia
  1. Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK
  1. Correspondence to Dr N Kalia, Centre for Cardiovascular Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK; n.kalia{at}bham.ac.uk

Abstract

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.

Design: 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 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 the α4β1/VCAM-1 pathway mediates HSC recruitment to injured liver. Manipulating this pathway may enhance delivery of HSCs to the liver.

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Footnotes

  • Funding This research and DPJK were funded by the UK Medical Research Council.

  • Competing interests None.

  • Ethics approval All procedures using mice were performed in accordance with the UK Animals (Scientific Procedures) Act of 1986 (Project Licence Numbers 40/2749 and 40/2212).

  • Provenance and Peer review Not commissioned; externally peer reviewed.

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