Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?

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  • Guido Moll
    Division of Clinical Immunology and Transfusion Medicine Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden
  • Jessica J. Alm
    Hematology and Regenerative Medicine Centre at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • Lindsay C. Davies
    Wound Biology Group Tissue Engineering and Reparative Dentistry Cardiff University, Cardiff, United Kingdom
  • Lena von Bahr
    Hematology and Regenerative Medicine Centre at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • Nina Heldring
    Hematology and Regenerative Medicine Centre at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • Lillemor Stenbeck-Funke
    Department of Immunology Genetics and Pathology Uppsala University, Uppsala, Sweden
  • Osama A. Hamad
    Department of Immunology Genetics and Pathology Uppsala University, Uppsala, Sweden
  • Robin Hinsch
    Hematology and Regenerative Medicine Centre at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • Lech Ignatowicz
    Department of Microbiology Tumor and Cell Biology (MTC) Karolinska Institutet, Stockholm, Sweden
  • Matthew Locke
    Wound Biology Group Tissue Engineering and Reparative Dentistry Cardiff University, Cardiff, United Kingdom
  • Helena Lönnies
    Division of Clinical Immunology and Transfusion Medicine Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden
  • John D. Lambris
    Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
  • Yuji Teramura
    Department of Immunology Genetics and Pathology Uppsala University, Uppsala, Sweden
  • Kristina Nilsson-Ekdahl
    Department of Immunology Genetics and Pathology Uppsala University, Uppsala, Sweden
  • Bo Nilsson
    Department of Immunology Genetics and Pathology Uppsala University, Uppsala, Sweden
  • Katarina Blanc
    Division of Clinical Immunology and Transfusion Medicine Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden

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<jats:title>Abstract</jats:title> <jats:p>We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement-mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation. Stem Cells  2014;32:2430–2442</jats:p>

Journal

  • Stem Cells

    Stem Cells 32 (9), 2430-2442, 2014-08-18

    Oxford University Press (OUP)

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