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Inflammation Research

, Volume 68, Issue 2, pp 167–176 | Cite as

Empowering the immune fate of bone marrow mesenchymal stromal cells: gene and protein changes

  • Mehdi NajarEmail author
  • Yassine Ouhaddi
  • Fatima Bouhtit
  • Rahma Melki
  • Hassan Afif
  • Noureddine Boukhatem
  • Makram Merimi
  • Hassan FahmiEmail author
Original Research Paper
  • 122 Downloads

Abstract

Objective and design

Bone marrow mesenchymal stromal cells (BM-MSCs) are referred as a promising immunotherapeutic cell product. New approaches using empowered MSCs should be developed as for the treatment or prevention of different immunological diseases. Such preconditioning by new licensing stimuli will empower the immune fate of BM-MSCs and, therefore, promote a better and more efficient biological. Here, our main goal was to establish the immunological profile of BM-MSCs following inflammatory priming and in particular their capacity to adjust their immune-related proteome and transcriptome.

Material and methods

To run this study, we have used BM-MSC cell cultures, a pro-inflammatory cytokine cocktail priming, flow cytometry analysis, qPCR and ELISA techniques.

Results

Different expression levels of several immunological mediators such as COX-1, COX-2, LIF, HGF, Gal-1, HO-1, IL-11, IL-8, IL-6 and TGF-β were constitutively observed in BM-MSCs. Inflammation priming substantially but differentially modulated the gene and protein expression profiles of these mediators. Thus, expressions of COX-2, LIF, HGF, IL-11, IL-8 and IL-6 were highly increased/induced and those of COX-1, Gal-1, and TGF-β were reduced.

Conclusions

Collectively, we demonstrated that BM-MSCs are endowed with a specific and modular regulatory machinery which is potentially involved in immunomodulation. Moreover, BM-MSCs are highly sensitive to inflammation and respond to such signal by properly adjusting their gene and protein expression of regulatory factors. Using such preconditioning may empower the immune fate of MSCs and, therefore, enhance their value for cell-based immunotherapy.

Keywords

Bone marrow Mesenchymal stromal cells Immunomodulation Regulatory mediators Inflammation priming 

Notes

Acknowledgements

We gratefully acknowledge the support received from the “Fonds de la Recherche Scientifique (FNRS)”, and its Télévie program. We also thank the Canadian Institutes of Health Research (Grant MOP-130293).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Via AG, Frizziero A, Oliva F. Biological properties of mesenchymal stem cells from different sources. Muscles Ligaments Tendons J. 2012;2(3):154–62.Google Scholar
  2. 2.
    Zhao Q, Ren H, Han Z. Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother. 2016;2(1):3–20.Google Scholar
  3. 3.
    Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009;20(5–6):419–27.  https://doi.org/10.1016/j.cytogfr.2009.10.002.Google Scholar
  4. 4.
    Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009–16.  https://doi.org/10.1038/ni.3002.Google Scholar
  5. 5.
    Luk F, de Witte SF, Bramer WM, Baan CC, Hoogduijn MJ. Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review. Expert Rev Clin Immunol. 2015;11(5):617–36.  https://doi.org/10.1586/1744666X.2015.1029458.Google Scholar
  6. 6.
    Fayyad-Kazan H, Faour WH, Badran B, Lagneaux L, Najar M. The immunomodulatory properties of human bone marrow-derived mesenchymal stromal cells are defined according to multiple immunobiological criteria. Inflamm Res. 2016;65(6):501–10.  https://doi.org/10.1007/s00011-016-0933-2.Google Scholar
  7. 7.
    Najar M, Raicevic G, Crompot E, Fayyad-Kazan H, Bron D, Toungouz M, et al. The immunomodulatory potential of mesenchymal stromal cells: a story of a regulatory network. J Immunother. 2016;39(2):45–59.  https://doi.org/10.1097/CJI.0000000000000108.Google Scholar
  8. 8.
    Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L. Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy. 2016;18(2):160–71.  https://doi.org/10.1016/j.jcyt.2015.10.011.Google Scholar
  9. 9.
    Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Bone marrow mesenchymal stromal cells induce proliferative, cytokinic and molecular changes during the T cell response: the importance of the IL-10/CD210 axis. Stem Cell Rev. 2015;11(3):442–52.  https://doi.org/10.1007/s12015-014-9567-3.Google Scholar
  10. 10.
    Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming. Stem Cell Rev. 2012;8(4):1188–98.  https://doi.org/10.1007/s12015-012-9408-1.Google Scholar
  11. 11.
    Qi K, Li N, Zhang Z, Melino G. Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response. Cell Immunol. 2018;326:86–93.  https://doi.org/10.1016/j.cellimm.2017.11.010.Google Scholar
  12. 12.
    Holan V, Hermankova B, Bohacova P, Kossl J, Chudickova M, Hajkova M, et al. Distinct immunoregulatory mechanisms in mesenchymal stem cells: role of the cytokine environment. Stem Cell Rev. 2016;12(6):654–63.  https://doi.org/10.1007/s12015-016-9688-y.Google Scholar
  13. 13.
    Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.  https://doi.org/10.1038/emm.2013.94.Google Scholar
  14. 14.
    Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402.  https://doi.org/10.1016/j.stem.2013.09.006.Google Scholar
  15. 15.
    Najar M, Krayem M, Merimi M, Burny A, Meuleman N, Bron D, et al. Insights into inflammatory priming of mesenchymal stromal cells: functional biological impacts. Inflamm Res. 2018;67(6):467–77.  https://doi.org/10.1007/s00011-018-1131-1.Google Scholar
  16. 16.
    Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci. 1997;2:d12–26.Google Scholar
  17. 17.
    Last-Barney K, Homon CA, Faanes RB, Merluzzi VJ. Synergistic and overlapping activities of tumor necrosis factor-alpha and IL-1. J Immunol. 1988;141(2):527–30.Google Scholar
  18. 18.
    Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.  https://doi.org/10.1189/jlb.0603252.Google Scholar
  19. 19.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.  https://doi.org/10.1080/14653240600855905.Google Scholar
  20. 20.
    Pankajakshan D, Agrawal DK. Mesenchymal stem cell paracrine factors in vascular repair and regeneration. J Biomed Technol Res. 2014.  https://doi.org/10.19104/jbtr.2014.107.Google Scholar
  21. 21.
    Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014;21(2):216–25.  https://doi.org/10.1038/cdd.2013.158.Google Scholar
  22. 22.
    Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond). 2005;2:8.  https://doi.org/10.1186/1476-9255-2-8.Google Scholar
  23. 23.
    Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15(6):641–8.  https://doi.org/10.1016/j.jcyt.2013.02.006.Google Scholar
  24. 24.
    Suga H, Matsumoto D, Eto H, Inoue K, Aoi N, Kato H, et al. Functional implications of CD34 expression in human adipose-derived stem/progenitor cells. Stem Cells Dev. 2009;18(8):1201–10.  https://doi.org/10.1089/scd.2009.0003.Google Scholar
  25. 25.
    W PMSHRMMG. SK. Adult mesenchymal stem cells and cell surface characterization—a systematic review of the literature. Open Orthop J. 2011;5(Suppl 2):253–60.  https://doi.org/10.2174/1874325001105010253.Google Scholar
  26. 26.
    Najar M, Raicevic G, Andre T, Fayyad-Kazan H, Pieters K, Bron D, et al. Mesenchymal stromal cells from the foreskin: tissue isolation, cell characterization and immunobiological properties. Cytotherapy. 2016;18(3):320–35.  https://doi.org/10.1016/j.jcyt.2015.11.013.Google Scholar
  27. 27.
    Sundin M, D’Arcy P, Johansson CC, Barrett AJ, Lonnies H, Sundberg B, et al. Multipotent mesenchymal stromal cells express FoxP3: a marker for the immunosuppressive capacity? J Immunother. 2011;34(4):336–42.  https://doi.org/10.1097/CJI.0b013e318217007c.Google Scholar
  28. 28.
    Regateiro FS, Cobbold SP, Waldmann H. CD73 and adenosine generation in the creation of regulatory microenvironments. Clin Exp Immunol. 2013;171(1):1–7.  https://doi.org/10.1111/j.1365-2249.2012.04623.x.Google Scholar
  29. 29.
    Lee JJ, Jeong HJ, Kim MK, Wee WR, Lee WW, Kim SU, et al. CD39-mediated effect of human bone marrow-derived mesenchymal stem cells on the human Th17 cell function. Purinergic Signal. 2014;10(2):357–65.  https://doi.org/10.1007/s11302-013-9385-0.Google Scholar
  30. 30.
    Szyska M, Na IK. Bone marrow GvHD after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:118.  https://doi.org/10.3389/fimmu.2016.00118.Google Scholar
  31. 31.
    Wood KJ, Issa F, Hester J. Understanding stem cell immunogenicity in therapeutic applications. Trends Immunol. 2016;37(1):5–16.  https://doi.org/10.1016/j.it.2015.11.005.Google Scholar
  32. 32.
    Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31(10):890–6.Google Scholar
  33. 33.
    Romieu-Mourez R, Francois M, Boivin MN, Stagg J, Galipeau J. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-gamma, TGF-beta, and cell density. J Immunol. 2007;179(3):1549–58.Google Scholar
  34. 34.
    Kim JH, Jo CH, Kim HR, Hwang YI. Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue. Stem Cells Int. 2018;2018:8429042.  https://doi.org/10.1155/2018/8429042.Google Scholar
  35. 35.
    Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest. 2002;109(3):295–9.  https://doi.org/10.1172/JCI14941.Google Scholar
  36. 36.
    Briones J, Novelli S, Sierra J. T-cell costimulatory molecules in acute-graft-versus host disease: therapeutic implications. Bone Marrow Res. 2011;2011:976793.  https://doi.org/10.1155/2011/976793.Google Scholar
  37. 37.
    Castro-Manrreza ME, Mayani H, Monroy-Garcia A, Flores-Figueroa E, Chavez-Rueda K, Legorreta-Haquet V, et al. Human mesenchymal stromal cells from adult and neonatal sources: a comparative in vitro analysis of their immunosuppressive properties against T cells. Stem Cells Dev. 2014;23(11):1217–32.  https://doi.org/10.1089/scd.2013.0363.Google Scholar
  38. 38.
    Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60.  https://doi.org/10.1038/nbt.2816.Google Scholar
  39. 39.
    Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6(5):552–70.  https://doi.org/10.4252/wjsc.v6.i5.552.Google Scholar
  40. 40.
    Shi Y, Cao J, Wang Y. Rethinking regeneration: empowerment of stem cells by inflammation. Cell Death Differ. 2015;22(12):1891–2.  https://doi.org/10.1038/cdd.2015.127.Google Scholar
  41. 41.
    Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB. Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One. 2010;5(2):e9016.  https://doi.org/10.1371/journal.pone.0009016.Google Scholar
  42. 42.
    Crop MJ, Baan CC, Korevaar SS, Ijzermans JN, Pescatori M, Stubbs AP, et al. Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells. Clin Exp Immunol. 2010;162(3):474–86.  https://doi.org/10.1111/j.1365-2249.2010.04256.x.Google Scholar
  43. 43.
    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(2):386–98.  https://doi.org/10.1634/stemcells.2005-0008.Google Scholar
  44. 44.
    Chen K, Wang D, Du WT, Han ZB, Ren H, Chi Y, et al. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol. 2010;135(3):448–58.  https://doi.org/10.1016/j.clim.2010.01.015.Google Scholar
  45. 45.
    Chabannes D, Hill M, Merieau E, Rossignol J, Brion R, Soulillou JP, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood. 2007;110(10):3691–4.  https://doi.org/10.1182/blood-2007-02-075481.Google Scholar
  46. 46.
    Patel SR, Copland IB, Garcia MA, Metz R, Galipeau J. Human mesenchymal stromal cells suppress T-cell proliferation independent of heme oxygenase-1. Cytotherapy. 2015;17(4):382–91.  https://doi.org/10.1016/j.jcyt.2014.11.010.Google Scholar
  47. 47.
    Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188(1):21–8.  https://doi.org/10.4049/jimmunol.1101029.Google Scholar
  48. 48.
    Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res. 2005;305(1):33–41.  https://doi.org/10.1016/j.yexcr.2004.12.013.Google Scholar
  49. 49.
    Hsu WT, Lin CH, Chiang BL, Jui HY, Wu KK, Lee CM. Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+ IFN-gamma+ CD4+ regulatory T cells to control transplant arteriosclerosis. J Immunol. 2013;190(5):2372–80.  https://doi.org/10.4049/jimmunol.1202996.Google Scholar
  50. 50.
    Liu FT. Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol. 2005;136(4):385–400.  https://doi.org/10.1159/000084545.Google Scholar
  51. 51.
    Sioud M, Mobergslien A, Boudabous A, Floisand Y. Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins. Int J Oncol. 2011;38(2):385–90.  https://doi.org/10.3892/ijo.2010.869.Google Scholar
  52. 52.
    Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev. 2015;26(5):533–44.  https://doi.org/10.1016/j.cytogfr.2015.07.001.Google Scholar
  53. 53.
    Nasef A, Mazurier C, Bouchet S, Francois S, Chapel A, Thierry D, et al. Leukemia inhibitory factor: role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008;253(1–2):16–22.  https://doi.org/10.1016/j.cellimm.2008.06.002.Google Scholar
  54. 54.
    Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.Google Scholar
  55. 55.
    Skibinski G. The role of hepatocyte growth factor/c-met interactions in the immune system. Arch Immunol Ther Exp (Warsz). 2003;51(5):277–82.Google Scholar
  56. 56.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.  https://doi.org/10.1146/annurev.immunol.24.021605.090737.Google Scholar
  57. 57.
    Xu C, Yu P, Han X, Du L, Gan J, Wang Y, et al. TGF-beta promotes immune responses in the presence of mesenchymal stem cells. J Immunol. 2014;192(1):103–9.  https://doi.org/10.4049/jimmunol.1302164.Google Scholar
  58. 58.
    Wu J, Xie A, Chen W. Cytokine regulation of immune tolerance. Burns Trauma. 2014;2(1):11–7.  https://doi.org/10.4103/2321-3868.124771.Google Scholar
  59. 59.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878–88.  https://doi.org/10.1016/j.bbamcr.2011.01.034.Google Scholar
  60. 60.
    Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–57.  https://doi.org/10.1038/ni.3153.Google Scholar
  61. 61.
    Zhukareva V, Obrocka M, Houle JD, Fischer I, Neuhuber B. Secretion profile of human bone marrow stromal cells: donor variability and response to inflammatory stimuli. Cytokine. 2010;50(3):317–21.  https://doi.org/10.1016/j.cyto.2010.01.004.Google Scholar
  62. 62.
    Najar M, Rouas R, Raicevic G, Boufker HI, Lewalle P, Meuleman N, et al. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy. 2009;11(5):570–83.  https://doi.org/10.1080/14653240903079377.Google Scholar
  63. 63.
    Putoczki T, Ernst M. More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer. J Leukoc Biol. 2010;88(6):1109–17.  https://doi.org/10.1189/jlb.0410226.Google Scholar
  64. 64.
    Hill GR, Cooke KR, Teshima T, Crawford JM, Keith JC Jr, Brinson YS, et al. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation. J Clin Invest. 1998;102(1):115–23.  https://doi.org/10.1172/JCI3132.Google Scholar
  65. 65.
    Teshima T, Hill GR, Pan L, Brinson YS, van den Brink MR, Cooke KR, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest. 1999;104(3):317–25.  https://doi.org/10.1172/JCI7111.Google Scholar
  66. 66.
    Auletta JJ, Eid SK, Wuttisarnwattana P, Silva I, Metheny L, Keller MD, et al. Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation. Stem Cells. 2015;33(2):601–14.  https://doi.org/10.1002/stem.1867.Google Scholar
  67. 67.
    Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 2004;25(2):75–84.  https://doi.org/10.1016/j.it.2003.12.005.Google Scholar
  68. 68.
    Najar M, Raicevic G, Fayyad-Kazan H, De Bruyn C, Bron D, Toungouz M, et al. Impact of different mesenchymal stromal cell types on T-cell activation, proliferation and migration. Int Immunopharmacol. 2013;15(4):693–702.  https://doi.org/10.1016/j.intimp.2013.02.020.Google Scholar
  69. 69.
    Qiu Y, Guo J, Mao R, Chao K, Chen BL, He Y, et al. TLR3 preconditioning enhances the therapeutic efficacy of umbilical cord mesenchymal stem cells in TNBS-induced colitis via the TLR3-Jagged-1-Notch-1 pathway. Mucosal Immunol. 2017;10(3):727–42.  https://doi.org/10.1038/mi.2016.78.Google Scholar
  70. 70.
    Han X, Yang Q, Lin L, Xu C, Zheng C, Chen X, et al. Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ. 2014;21(11):1758–68.  https://doi.org/10.1038/cdd.2014.85.Google Scholar
  71. 71.
    Sivanathan KN, Rojas-Canales DM, Hope CM, Krishnan R, Carroll RP, Gronthos S, et al. Interleukin-17A-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells. 2015;33(9):2850–63.  https://doi.org/10.1002/stem.2075.Google Scholar
  72. 72.
    Kavanagh DP, Robinson J, Kalia N. Mesenchymal stem cell priming: fine-tuning adhesion and function. Stem Cell Rev. 2014;10(4):587–99.  https://doi.org/10.1007/s12015-014-9510-7.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Mehdi Najar
    • 1
    Email author
  • Yassine Ouhaddi
    • 1
  • Fatima Bouhtit
    • 2
  • Rahma Melki
    • 2
  • Hassan Afif
    • 1
  • Noureddine Boukhatem
    • 2
  • Makram Merimi
    • 2
    • 3
  • Hassan Fahmi
    • 1
    Email author
  1. 1.Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Department of MedicineUniversity of MontrealMontrealCanada
  2. 2.Laboratory of Physiology, Ethnopharmacology and Genetics, Faculty of SciencesUniversity Mohammed PremierOujdaMorocco
  3. 3.Laboratory of Experimental Hematology, Jules Bordet InstituteUniversité Libre de BruxellesBrusselsBelgium

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