TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb

Authors

  • Ashish S. Patel,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Alberto Smith,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Silvia Nucera,

    1. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
    2. Vita-Salute University, Milan, Italy
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  • Daniela Biziato,

    1. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
    2. Vita-Salute University, Milan, Italy
    3. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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  • Prakash Saha,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Rizwan Q. Attia,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Julia Humphries,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Katherine Mattock,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Steven P. Grover,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Oliver T. Lyons,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Luca G. Guidotti,

    1. Immunopathogenesis of Liver Infections Unit, San Raffaele Scientific Institute, Milan, Italy
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  • Richard Siow,

    1. Vascular Biology Group, Cardiovascular Division, King's College London, UK
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  • Aleksandar Ivetic,

    1. Membrane/Cytoskeletal Signalling Group, Cardiovascular Division, King's College London, UK
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  • Stuart Egginton,

    1. School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK
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  • Matthew Waltham,

    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
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  • Luigi Naldini,

    1. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
    2. Vita-Salute University, Milan, Italy
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  • Michele De Palma,

    1. Angiogenesis and Tumor Targeting Unit, and HSR-TIGET, San Raffaele Scientific Institute, Milan, Italy
    2. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
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    • These authors contributed equally to this work.

  • Bijan Modarai

    Corresponding author
    1. Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence and the Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, UK
    • Tel: +44 207 1880216; Fax: +44 207 9288742

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    • These authors contributed equally to this work.


Abstract

A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients.

→See accompanying articles http://dx.doi.org/10.1002/emmm.201302695 and http://dx.doi.org/10.1002/emmm.201302794

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