title: Human mesenchymal stem cells are recruited to injured liver in a β1-integrin and CD44 dependent manner.
abstract: Human bone marrow mesenchymal stem cells (hMSCs) have shown benefit in clinical trials of patients with liver disease. Efficient delivery of cells to target organs is critical to improving their effectiveness. This requires an understanding of the mechanisms governing cellular engraftment into the liver. Binding of hMSCs to normal/injured liver tissue, purified extracellular matrices, and human hepatic sinusoidal endothelial cells (HSECs) were quantified in static and flow conditions. To define the mechanisms underpinning hMSC interactions, neutralizing adhesion molecule antibodies were used. Fluorescently labelled hMSCs were infused intraportally into CCl(4) -injured mice with and without neutralizing antibodies. hMSCs expressed high levels of CD29/β1-integrin and CD44. Using liver tissue binding assays, hMSC adhesion was greatest in diseased human liver versus normal liver (32.2 cells/field versus 20.5 cells/field [P = 0.048]). Neutralizing antibodies against CD29 and CD44 reduced hMSC binding to diseased liver by 34% and 35%, respectively (P = 0.05). hMSCs rolled at 528 μm/second on HSECs in flow assays. This rolling was abolished by CD29 blockade on hMSCs and vascular cell adhesion molecule-1 (VCAM-1) blockade on HSECs. Firm adhesion to HSECs was reduced by CD29 (55% [P = 0.002]) and CD44 (51% [P = 0.04]) blockade. Neutralizing antibodies to CD29 and CD44 reduced hepatic engraftment of hMSCs in murine liver from 4.45 cells/field to 2.88 cells/field (P = 0.025) and 2.35 cells/field (P = 0.03), respectively. hMSCs expressed modest levels of chemokine receptors including CCR4, CCR5, and CXCR3, but these made little contribution to hMSC adhesion in this setting.
  
  
  CONCLUSIONS
  hMSCs bind preferentially to injured liver. Rolling of hMSCs is regulated by CD29/VCAM-1, whereas CD29/CD44 interactions with VCAM-1, fibronectin, and hyaluronan on HSECs determine firm adhesion both in vitro and in vivo as demonstrated using a murine model of liver injury.
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK. v.s.s.aldridge@bham.ac.uk
authors.forename: Victoria
authors.initials: V
authors.lastname: Aldridge
authors.forename: Abhilok
authors.initials: A
authors.lastname: Garg
authors.forename: Nicholas
authors.initials: N
authors.lastname: Davies
authors.forename: David C
authors.initials: DC
authors.lastname: Bartlett
authors.forename: Janine
authors.initials: J
authors.lastname: Youster
authors.forename: Heather
authors.initials: H
authors.lastname: Beard
authors.forename: Dean P
authors.initials: DP
authors.lastname: Kavanagh
authors.forename: Neena
authors.initials: N
authors.lastname: Kalia
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
mesh_terms: D000818:Animals; D002465:Cell Movement; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D019012:Integrin beta1 / Q000502:physiology*; D008099:Liver / Q000293:injuries* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018960:Hyaluronan Receptors; D019012:Integrin beta1