title: T-cell-pre-stimulated monocytes promote neovascularisation in a murine hind limb ischaemia model.
abstract: OBJECTIVE
  Monocytes play a significant role in neovascularisation. The stimuli that differentiate monocytes along a pro-angio-/arteriogenic-supporting pathway are currently unclear. We investigated whether pre-stimulation of human monocytes with soluble T-cell-derived factors improves revascularisation in murine hind limb ischaemia as a new option for therapeutic angio- and arteriogenesis.
  
  
  METHODS
  Human monocytes were cultured with or without soluble T-cell-derived factors. Unstimulated and pre-stimulated monocytes were transfused after induction of hind limb ischaemia in nude mice.
  
  
  METHODS
  Blood flow was measured with laser Doppler perfusion imaging. Collaterals were visualised by immunohistochemistry and angiography. Monocytes were characterised by flowcytometry and Bio-Plex assays.
  
  
  RESULTS
  Transfusion of T-cell-pre-stimulated monocytes significantly improved blood flow recovery after hind limb ischaemia and increased collateral size and collateral and capillary number in the post-ischaemic paw. Pre-stimulated monocytes produced a wide variety of factors that support neovascularisation such as platelet-derived growth factor-BB, vascular-endothelial growth factor, interleukin-4 and tumour necrosis factor-α. Few transfused human cells were detected in the muscle tissue, suggesting that paracrine rather than direct effects appear responsible for the enhanced recovery of blood flow observed.
  
  
  CONCLUSIONS
  These results show a beneficial role for T-cell-pre-stimulated monocytes in neovascularisation, rendering the monocyte a potential candidate for regenerative cell therapy that promotes revascularisation in peripheral arterial disease patients.
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Hellingman
authors.forename: J J
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: R T
authors.initials: RT
authors.lastname: van Beem
authors.forename: J F
authors.initials: JF
authors.lastname: Hamming
authors.forename: W E
authors.initials: WE
authors.lastname: Fibbe
authors.forename: P H A
authors.initials: PH
authors.lastname: Quax
authors.forename: S B
authors.initials: SB
authors.lastname: Geutskens
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001783:Blood Flow Velocity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002196:Capillaries / Q000276:immunology / Q000503:physiopathology; D002478:Cells, Cultured; D003097:Collateral Circulation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006614:Hindlimb; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000000981:diagnostic imaging / Q000276:immunology / Q000503:physiopathology / Q000601:surgery*; D017078:Laser-Doppler Flowmetry; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology / Q000637:transplantation*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D011859:Radiography; D012039:Regional Blood Flow; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D018950:Lipopolysaccharide Receptors