Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stem Cells

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

Leukemia volume 25, pages 648–654 (2011)Cite this article

Subjects

Abstract

Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  PubMed  Google Scholar 

  2. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D . Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103: 4619–4621.

    Article  CAS  PubMed  Google Scholar 

  3. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L . Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008; 111: 1327–1333.

    Article  CAS  PubMed  Google Scholar 

  4. Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 2007; 110: 2764–2767.

    Article  CAS  PubMed  Google Scholar 

  5. Wolf D, Wolf AM . Mesenchymal stem cells as cellular immunosuppressants. Lancet 2008; 371: 1553–1554.

    Article  PubMed  Google Scholar 

  6. Nauta AJ, Fibbe WE . Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499–3506.

    Article  CAS  PubMed  Google Scholar 

  7. Kang HS, Habib M, Chan J, Abavana C, Potian JA, Ponzio NM et al. A paradoxical role for IFN-gamma in the immune properties of mesenchymal stem cells during viral challenge. Exp Hematol 2005; 33: 796–803.

    Article  CAS  PubMed  Google Scholar 

  8. Sundin M, Orvell C, Rasmusson I, Sundberg B, Ringden O, Le Blanc K . Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Marrow Transplant 2006; 37: 1051–1059.

    Article  CAS  PubMed  Google Scholar 

  9. Deak E, Ruster B, Keller L, Eckert K, Fichtner I, Seifried E et al. Suspension medium influences interaction of mesenchymal stromal cells with endothelium and pulmonary toxicity after transplantation in mice. Cytotherapy 2010; 12: 260–264.

    Article  CAS  PubMed  Google Scholar 

  10. Tropel P, Noel D, Platet N, Legrand P, Benabid AL, Berger F . Isolation and characterisation of mesenchymal stem cells from adult mouse bone marrow. Exp Cell Res 2004; 295: 395–406.

    Article  CAS  PubMed  Google Scholar 

  11. Daubener W, Wanagat N, Pilz K, Seghrouchni S, Fischer HG, Hadding U . A new, simple, bioassay for human IFN-gamma. J Immunol Methods 1994; 168: 39–47.

    Article  CAS  PubMed  Google Scholar 

  12. Ding AH, Nathan CF, Stuehr DJ . Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 1988; 141: 2407–2412.

    CAS  PubMed  Google Scholar 

  13. Schroten H, Spors B, Hucke C, Stins M, Kim KS, Adam R et al. Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: inhibition of Staphylococcus aureus by activation of indoleamine 2,3-dioxygenase. Neuropediatrics 2001; 32: 206–210.

    Article  CAS  PubMed  Google Scholar 

  14. Daubener W, Spors B, Hucke C, Adam R, Stins M, Kim KS et al. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect Immun 2001; 69: 6527–6531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Adams O, Besken K, Oberdorfer C, MacKenzie CR, Takikawa O, Daubener W . Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections. J Virol 2004; 78: 2632–2636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Parsons CH, Szomju B, Kedes DH . Susceptibility of human fetal mesenchymal stem cells to Kaposi sarcoma-associated herpesvirus. Blood 2004; 104: 2736–2738.

    Article  CAS  PubMed  Google Scholar 

  17. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 2007; 109: 228–234.

    Article  CAS  PubMed  Google Scholar 

  18. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2: 141–150.

    Article  CAS  PubMed  Google Scholar 

  19. Muller A, Heseler K, Schmidt SK, Spekker K, Mackenzie CR, Daubener W . The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects. J Cell Mol Med 2009; 13: 1125–1135.

    Article  PubMed  Google Scholar 

  20. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.

    Article  CAS  PubMed  Google Scholar 

  21. Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC . Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia 2005; 19: 1597–1604.

    Article  CAS  PubMed  Google Scholar 

  22. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006; 24: 386–398.

    Article  CAS  PubMed  Google Scholar 

  23. Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol 2007; 179: 1595–1604.

    Article  CAS  PubMed  Google Scholar 

  24. Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176: 7761–7767.

    Article  CAS  PubMed  Google Scholar 

  25. Badillo AT, Peranteau WH, Heaton TE, Quinn C, Flake AW . Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft-versus-host disease. Br J Haematol 2008; 141: 224–234.

    Article  PubMed  Google Scholar 

  26. Prigozhina TB, Khitrin S, Elkin G, Eizik O, Morecki S, Slavin S . Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation. Exp Hematol 2008; 36: 1370–1376.

    Article  CAS  PubMed  Google Scholar 

  27. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.

    Article  CAS  PubMed  Google Scholar 

  28. Kaandorp CJ, Dinant HJ, van de Laar MA, Moens HJ, Prins AP, Dijkmans BA . Incidence and sources of native and prosthetic joint infection: a community based prospective survey. Ann Rheum Dis 1997; 56: 470–475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sia IG, Berbari EF . Infection and musculoskeletal conditions: osteomyelitis. Best Pract Res Clin Rheumatol 2006; 20: 1065–1081.

    Article  PubMed  Google Scholar 

  30. Muller I, Vaegler M, Holzwarth C, Tzaribatchev N, Pfister SM, Schutt B et al. Secretion of angiogenic proteins by human multipotent mesenchymal stromal cells and their clinical potential in the treatment of avascular osteonecrosis. Leukemia 2008; 22: 2054–2061.

    Article  CAS  PubMed  Google Scholar 

  31. Hebart H, Einsele H . Clinical aspects of CMV infection after stem cell transplantation. Hum Immunol 2004; 65: 432–436.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D Klostermann for technical assistance. Moreover, we want to acknowledge M Herten (Department of Orthopedics, Heinrich-Heine-University Düsseldorf) for performing chondrogenic differentiation assays and P Verde (Coordination Center for Clinical Trials, Heinrich-Heine-University Düsseldorf) for expert statistical advice. Human CMV was kindly provided by C Sinzger (Institute for Medical Virology, University of Tübingen, Germany) and Toxoplasma gondii tachyzoites were obtained from M Saathoff and HM Seitz (Institute for Medical Parasitology, University of Bonn, Germany). This work was supported by German Federal Ministry of Education and Research (BMBF) Grants nos. 01GN0990 (RM, DD), 01GM0873 (RM, DD), 01GN0951 (RS, WD), 01GN0952 (RH) and 01GN0949 (JS), German Research Council (DFG) Grant no. RU729 (WD) and the ‘Elterninitiative Kinderkrebsklinik Düsseldorf e.V.’ (RM).

Author information

Author notes

  1. D Dilloo

    Present address: 7Current address: Department of Pediatric Hematology and Oncology, University Children's Hospital, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.,

Authors and Affiliations

  1. Clinic of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany

    R Meisel, Ö Degistirici, H Bülle & D Dilloo

  2. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany

    S Brockers, K Heseler, C Woite, S Stuhlsatz, W Schwippert & W Däubener

  3. Department of Orthopedics, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany

    M Jäger

  4. Institute of Transplantation Diagnostics und Cell Therapeutics, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany

    R Sorg

  5. Institute of Transfusion Medicine and Immune Hematology, Johann-Wolfgang-Goethe-University, Frankfurt, Germany

    R Henschler

  6. Diabetes Center, Medical Clinic Innenstadt, Ludwig-Maximilians-University, Munich, Germany

    J Seissler

Authors
  1. R Meisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Brockers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Heseler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ö Degistirici
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Bülle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Woite
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Stuhlsatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W Schwippert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Sorg
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Henschler
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Seissler
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Dilloo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. W Däubener
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Meisel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author contributions

RM and WD designed research; RM, SB, KH, ÖD, HB, CW, SS, WS, MJ, RS, RH, JS, DD and WD performed research; RM, RS and WD analyzed data; and RM, DD and WD wrote the paper.

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meisel, R., Brockers, S., Heseler, K. et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 25, 648–654 (2011). https://doi.org/10.1038/leu.2010.310

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.310

Keywords

This article is cited by

Search

Advanced search

Quick links