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:

Mesenchymal Stem Cells

Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells

Bone Marrow Transplantation volume 32, pages 265–272 (2003)Cite this article

An Erratum to this article was published on 21 May 2004

Summary:

Adult mesenchymal stem cells (MSCs) have been suggested to decrease lymphocyte proliferation in vitro. We hypothesised that foetal MSCs (fMSCs) would have an immunosuppressive effect on allograft responses in vitro. Human MSCs were isolated and cultured from first-trimester foetal livers and characterised by flow cytometry. fMSC stained positive for CD29, CD44, CD166, CD105, SH-3 and SH-4, and negative for CD14, CD34 and CD45. When plated on adipogenic, chondrogenic and osteogenic media, fMSC differentiated into the respective cell lineage. Compared to adult MSC (aMSC), the proliferative capacity of fMSC was higher. Mitogen stimulation of PBL was inhibited by fMSC. The greatest inhibition (78%) was seen when 30 000 fMSCs were added to 150 000 lymphocytes stimulated by phytohaemagglutinin. Adult and fMSCs were added to mixed lymphocyte cultures (MLC) containing peripheral blood lymphocytes or foetal liver cells. Unlike aMSC, fMSCs did not inhibit MLC. fMSC could be culture-expanded several million folds with no loss of phenotype characteristics, which makes them ideal for ex vivo expansion. fMSC inhibit lymphocyte proliferation induced by mitogens, but not alloreactivity as measured by MLC.

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
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Caplan AI . Mesenchymal stem cells. J Orthop Res 1991; 9: 641–650.

    Article  CAS  Google Scholar 

  2. Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  3. Caplan AI . The mesengenic process. Clin Plast Surg 1994; 21: 429–435.

    CAS  PubMed  Google Scholar 

  4. Erices A, Conget P, Minguell JJ . Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235–242.

    Article  CAS  Google Scholar 

  5. Campagnoli C, Roberts IA, Kumar S et al. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98: 2396–2402.

    Article  CAS  Google Scholar 

  6. Young HE, Steele TA, Bray RA et al. Human pluripotent and progenitor cells display cell surface cluster differentiation markers CD10, CD13, CD56, and MHC class-I. Proc Soc Exp Biol Med 1999, 221: 63–71.

    Article  CAS  Google Scholar 

  7. Di Nicola M, Carlo-Stella C, Magni M et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  Google Scholar 

  8. Le Blanc K, Tammik C, Sundberg B et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompability complex. Scand J Immunol 2003; 57: 11–20.

    Article  CAS  Google Scholar 

  9. Devine SM, Bartholomew AM, Mahmud N et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001; 29: 244–255.

    Article  CAS  Google Scholar 

  10. Bartholomew A, Patil S, Mackay A et al. Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo. Hum Gene Ther 2001; 12: 1527–1541.

    Article  CAS  Google Scholar 

  11. Koc ON, Peters C, Aubourg P et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 1999; 27: 1675–1681.

    Article  CAS  Google Scholar 

  12. Mackenzie TC, Flake AW . Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep. Blood Cells Mol Dis 2001; 27: 601–604.

    Article  CAS  Google Scholar 

  13. Westgren M, Ek S, Bui TH et al. Establishment of a tissue bank for fetal stem cell transplantation. Acta Obstet Gynecol Scand 1994; 73: 385–388.

    Article  CAS  Google Scholar 

  14. Lennon DP HS, Bruder SP, Jaiswal N et al. Human and animal mesenchymal progenitor cells from bone marrow: identification of serum for optimal selection and proliferation. In Vitro Cell Dev Biol 1996; 32: 602–611.

    Article  Google Scholar 

  15. Prockop DJ . Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276: 71–74.

    Article  CAS  Google Scholar 

  16. Berg B, Ringdén O . Correlation between relative responses in mixed lymphocyte culture, HLA- D and DR typing, and graft survival in renal transplantation. Transplantation 1982; 33: 291–297.

    Article  CAS  Google Scholar 

  17. Greaves M, Janossy G, Doenhoff M . Selective triggering of human T and B lymphocytes in vitro by polyclonal mitogens. J Exp Med 1974; 140: 1–18.

    Article  CAS  Google Scholar 

  18. Ringdén O, Rynnel-Dagöö B . Activation of human B and T lymphocytes by protein A of Staphylococcus aureus. Eur J Immunol 1978; 8: 47–52.

    Article  Google Scholar 

  19. Conget PA, Minguell JJ . Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol 1999; 181: 67–73.

    Article  CAS  Google Scholar 

  20. Majumdar MK, Thiede MA, Mosca JD et al. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998; 176: 57–66.

    Article  CAS  Google Scholar 

  21. Krampera M, Glennie S, Dyson J et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; (in press).

  22. Bartholomew A, Sturgeon C, Siatskas M et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–48.

    Article  Google Scholar 

  23. Lun MT, Cochi S, Fioravanti D et al. Effect of cyclosporin A on B cell maturation and differentiation. Drugs Exp Clin Res 1991; 17: 493–500.

    CAS  PubMed  Google Scholar 

  24. Lindton B, Markling L, Ringdén O et al. Mixed lymphocyte culture of human fetal liver cells. Fetal Diagn Ther 2000; 15: 71–78.

    Article  CAS  Google Scholar 

  25. Hobbs JR, Hugh-Jones K, Barrett AJ et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; 2: 709–712.

    Article  CAS  Google Scholar 

  26. Hobbs JR . Bone marrow transplantation for inborn errors. Lancet 1981; 2: 735–739.

    Article  CAS  Google Scholar 

  27. Parkman R, Rappeport J, Geha R et al. Complete correction of the Wiskott–Aldrich syndrome by allogeneic bone-marrow transplantation. N Engl J Med 1978; 298: 921–927.

    Article  CAS  Google Scholar 

  28. Ringdén O, Groth CG, Erikson A et al. Ten years' experience of bone marrow transplantation for Gaucher disease. Transplantation 1995; 59: 864–870.

    Article  Google Scholar 

  29. Hoogerbrugge PM, Brouwer OF, Bordigoni P et al. Allogeneic bone marrow transplantation for lysosomal storage diseases. The European Group for Bone Marrow Transplantation. Lancet 1995; 345: 1398–1402.

    Article  CAS  Google Scholar 

  30. Touraine J, Raudrant D, Laplace S et al. Intrauterine transplantation for immunodeficiencies and hemoglobinopathies in man. In: Ringdén O, Hobbs J, Steward C (eds). Correction of Genetic Diseases by Transplantation 1997. COGENT: London, 1997, pp 163–173.

    Google Scholar 

  31. Westgren M, Ringden O, Bartmann P et al. Prenatal T-cell reconstitution after in utero transplantation with fetal liver cells in a patient with X-linked severe combined immunodeficiency. Am J Obstet Gynecol 2002; 187: 475–482.

    Article  Google Scholar 

  32. Horwitz EM, Gordon PL, Koo WK et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 2002; 99: 8932–8937.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Lola Markling for organising and distributing the foetal liver tissues and Osiris Therapeutics for providing antibodies.

This study was supported by grants from the Swedish Cancer Society (0070-B99-13XAC), The Children's Cancer Foundation (1997/073), the Swedish Medical Research Council (K2000-06X-05971-20A, K2001-06X11231-07B), the Tobias Foundation, the Stockholm Cancer Society, the FRF Foundation and by the European Commission Biomed 2 Programme (Eurofoetus project).

Author information

Authors and Affiliations

  1. Division of Clinical Immunology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden

    C Götherström, O Ringdén, C Tammik & K Le Blanc

  2. Centre for Allogenic Stem Cell Transplantation, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden

    O Ringdén & K Le Blanc

  3. Centre for Foetal Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden

    M Westgren

Authors
  1. C Götherström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Ringdén
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Westgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Tammik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Le Blanc
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Götherström, C., Ringdén, O., Westgren, M. et al. Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells. Bone Marrow Transplant 32, 265–272 (2003). https://doi.org/10.1038/sj.bmt.1704111

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704111

Keywords

This article is cited by

Search

Advanced search

Quick links