Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?§

Authors

  • Guido Moll,

    Corresponding author
    1. Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    • Division of Clinical Immunology and Transfusion Medicine F79, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
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    • Telephone: +46-8-5858-1361; Fax: +46-8-746-6699

  • Ida Rasmusson-Duprez,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Lena von Bahr,

    1. Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    2. Hematology Center, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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  • Anne-Marie Connolly-Andersen,

    1. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    2. Swedish Institute for Communicable Disease Control, Stockholm, Sweden
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  • Graciela Elgue,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Lillemor Funke,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Osama A. Hamad,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Helena Lönnies,

    1. Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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  • Peetra U. Magnusson,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Javier Sanchez,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Yuji Teramura,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Kristina Nilsson-Ekdahl,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Olle Ringdén,

    1. Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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  • Olle Korsgren,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Bo Nilsson,

    1. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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  • Katarina Le Blanc

    1. Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
    2. Hematology Center, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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  • Author contributions: G.M., I.R.D., K.N.E., O.K., and K.L.B.: designed the study and wrote the manuscript; O.R. and K.L.B.: led the clinical study; G.M., I.R.D., L.V.B., A.M.C.A., and J.S.: performed the research and analyzed the data; P.M., G.E., L.F., L.L., O.H., and Y.T.: assisted various experiments.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS April 20, 2012.

Abstract

Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0–3.0 × 106 cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells. Stem Cells2012;30:1565–1574

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