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Immunological impact of Wharton’s Jelly mesenchymal stromal cells and natural killer cell co-culture

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Abstract

Due to their easier isolation, multilineage potential, and immunomodulatory capacity, Wharton’s Jelly-derived mesenchymal stromal cells (WJ-MSCs) exhibit promising efficacy in the field of regenerative medicine and immunotherapy. Characterization of WJ-MSCs–natural killer (NK) cells crosstalk is required for ameliorating the medicinal value of WJ-MSCs. Here, we revealed that the outcome of WJ-MSCs–NK cells crosstalk varied according to the type of cytokines (IL-2, IL-12, IL-15 and IL-21) utilized to activate NK cells. Differently activated NK cells exerted distinct cytotoxicities against WJ-MSCs causing their probable death. Cell surface ligands (CD112, CD155, ULPB-3) and receptors (LAIR, CD226, CD314, CD335, CD336 and CD337) governing the interaction between NK cells and their targets, exhibited altered expression profiles following the co-culture with WJ-MSCs. Although partly inhibited NK cell proliferation, WJ-MSCs enhanced activated NK-cell-mediated secretion of IFN-γ and TNF-α. Moreover, WJ-MSCs reinforced NK cells’ degranulation as well as secretion of perforin and granzymes. On the other hand, WJ-MSCs displayed only slight increase in ROS generation but significant decrease in A1 and C1 serpins expression following co-culture with activated NK cells. Altogether, our results highlight that WJ-MSCs–NK cells interaction may affect both cell type features and, therefore, their therapeutic properties.

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References

  1. Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317. https://doi.org/10.1080/14653240600855905

    Article  PubMed  CAS  Google Scholar 

  2. Pittenger MF (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147. https://doi.org/10.1126/science.284.5411.143

    Article  PubMed  CAS  Google Scholar 

  3. Mennan C, Wright K, Bhattacharjee A et al (2013) Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord. Biomed Res Int 2013:916136. https://doi.org/10.1155/2013/916136

    Article  PubMed  PubMed Central  Google Scholar 

  4. Weiss ML, Anderson C, Medicetty S et al (2008) Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells 26:2865–2874. https://doi.org/10.1634/stemcells.2007-1028

    Article  PubMed  CAS  Google Scholar 

  5. Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB (2010) Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS ONE 5:e9016. https://doi.org/10.1371/journal.pone.0009016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. La Rocca G, Anzalone R, Corrao S et al (2009) Isolation and characterization of Oct-4+/HLA-G + mesenchymal stem cells from human umbilical cord matrix: differentiation potential and detection of new markers. Histochem Cell Biol 131:267–282. https://doi.org/10.1007/s00418-008-0519-3

    Article  PubMed  CAS  Google Scholar 

  7. Tyndall A, Walker UA, Cope A et al (2007) Immunomodulatory properties of mesenchymal stem cells: a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005. Arthritis Res Ther 9:301. https://doi.org/10.1186/ar2103

    Article  PubMed  PubMed Central  Google Scholar 

  8. Auletta JJ, Eid SK, Wuttisarnwattana P et al (2015) Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation. Stem Cells 33:601–614. https://doi.org/10.1002/stem.1867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Verneris MR (2013) Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL. Hematol Am Soc Hematol Educ Progr 2013:335–341. https://doi.org/10.1182/asheducation-2013.1.335

    Article  Google Scholar 

  10. de Rham C, Ferrari-Lacraz S, Jendly S et al (2007) The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors. Arthritis Res Ther 9:R125. https://doi.org/10.1186/ar2336

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Joyce MG, Sun PD (2011) The structural basis of ligand recognition by natural killer cell receptors. J Biomed Biotechnol 2011:203628. https://doi.org/10.1155/2011/203628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Solana R, Casado JG, Delgado E et al (2007) Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands. Cancer Immunol Immunother 56:101–109. https://doi.org/10.1007/s00262-006-0141-y

    Article  PubMed  CAS  Google Scholar 

  13. Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735–747. https://doi.org/10.1038/nri911

    Article  PubMed  CAS  Google Scholar 

  14. Biron CA, Nguyen KB, Pien GC et al (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220. https://doi.org/10.1146/annurev.immunol.17.1.189

    Article  PubMed  CAS  Google Scholar 

  15. Sotiropoulou P, Perez S, Gritzapis AD et al (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24:74–85. https://doi.org/10.1634/stemcells.2004-0359

    Article  PubMed  Google Scholar 

  16. Spaggiari GM, Capobianco A, Becchetti S et al (2006) Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107:1484–1490. https://doi.org/10.1182/blood-2005-07-2775.Supported

    Article  PubMed  CAS  Google Scholar 

  17. Lupatov AY, Kim YS, Bystrykh OA et al (2017) Effect of fibroblast-like cells of mesenchymal origin of cytotoxic activity of lymphocytes against NK-sensitive target cells. Bull Exp Biol Med 162:552–557. https://doi.org/10.1007/s10517-017-3658-5

    Article  PubMed  CAS  Google Scholar 

  18. De Bruyn C, Najar M, Raicevic G et al (2011) A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton’s jelly without enzymatic treatment. Stem Cells Dev 20:547–557. https://doi.org/10.1089/scd.2010.0260

    Article  PubMed  CAS  Google Scholar 

  19. Krampera M, Galipeau J, Shi Y et al (2013) Immunological characterization of multipotent mesenchymal stromal cells—the international society for cellular therapy (ISCT) working proposal. Cytotherapy 15:1054–1061. https://doi.org/10.1016/j.jcyt.2013.02.010

    Article  PubMed  Google Scholar 

  20. Bouchlaka MN, Redelman D, Murphy WJ (2010) Immunotherapy following hematopoietic stem cell transplantation: potential for synergistic effects. Immunotherapy 2:399–418. https://doi.org/10.2217/imt.10.20

    Article  PubMed  CAS  Google Scholar 

  21. Ribeiro A, Laranjeira P, Mendes S et al (2013) Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther 4:125–141. https://doi.org/10.1186/scrt336

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Abdelrazik H, Spaggiari GM, Chiossone L, Moretta L (2011) Mesenchymal stem cells expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell proliferation and function. Eur J Immunol 41:3281–3290. https://doi.org/10.1002/eji.201141542

    Article  PubMed  CAS  Google Scholar 

  23. Yoon SR, Kim T-D, Choi I (2015) Understanding of molecular mechanisms in natural killer cell therapy. Exp Mol Med 47:e141. https://doi.org/10.1038/emm.2014.114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wu J, Song Y, Bakker AB et al (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285:730–732

    Article  PubMed  CAS  Google Scholar 

  25. Chieregato K, Albiero E, Castegnaro S et al (2012) A study on mutual interaction between cytokine induced killer cells and umbilical cord-derived mesenchymal cells: implication for their in-vivo use. Blood Cells Mol Dis 49:159–165. https://doi.org/10.1016/j.bcmd.2012.05.009

    Article  PubMed  CAS  Google Scholar 

  26. Giuliani M, Bennaceur-Griscelli A, Nanbakhsh A et al (2014) TLR ligands stimulation protects MSC from NK killing. Stem Cells 32:290–300. https://doi.org/10.1002/stem.1563

    Article  PubMed  CAS  Google Scholar 

  27. Rasmusson I, Ringdén O, Sundberg B, Le Blanc K (2003) Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76:1208–1213. https://doi.org/10.1097/01.TP.0000082540.43730.80

    Article  PubMed  Google Scholar 

  28. Hoogduijn MJ, Roemeling-van Rhijn M, Korevaar SS et al (2011) Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies. Hum Gene Ther 22:1587–1591. https://doi.org/10.1089/hum.2011.039

    Article  PubMed  CAS  Google Scholar 

  29. Poggi A, Prevosto C, Massaro A-M et al (2005) Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. J Immunol 175:6352–6360. https://doi.org/10.4049/jimmunol.175.10.6352

    Article  PubMed  CAS  Google Scholar 

  30. Jewett A, Arasteh A, Tseng HC et al (2010) Strategies to rescue mesenchymal stem cells (MSCs) and dental pulp stem cells (DPSCs) from NK cell mediated cytotoxicity. PLoS ONE 5:1–14. https://doi.org/10.1371/journal.pone.0009874

    Article  CAS  Google Scholar 

  31. Najar M, Rouas R, Raicevic G et al (2009) 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 11:570–583. https://doi.org/10.1080/14653240903079377

    Article  PubMed  CAS  Google Scholar 

  32. Poggi A, Zocchi MR (2014) NK cell autoreactivity and autoimmune diseases. Front Immunol 5:27. https://doi.org/10.3389/fimmu.2014.00027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Crop MJ, Korevaar SS, de Kuiper R et al (2011) Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant 20:1547–1559. https://doi.org/10.3727/096368910X564076

    Article  PubMed  Google Scholar 

  34. Moretta A, Bottino C, Vitale M et al (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223. https://doi.org/10.1146/annurev.immunol.19.1.197

    Article  PubMed  CAS  Google Scholar 

  35. Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23:255–259. https://doi.org/10.1038/sj.emboj.7600019

    Article  PubMed  CAS  Google Scholar 

  36. Bottino C, Castriconi R, Pende D et al (2003) Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198:557–567. https://doi.org/10.1084/jem.20030788

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. DelaRosa O, Sánchez-Correa B, Morgado S et al (2012) Human adipose-derived stem cells impair natural killer cell function and exhibit low susceptibility to natural killer-mediated lysis. Stem Cells Dev 21:1333–1343. https://doi.org/10.1089/scd.2011.0139

    Article  PubMed  CAS  Google Scholar 

  38. Götherström C, Lundqvist A, Duprez IR et al (2011) Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways. Cytotherapy 13:269–278. https://doi.org/10.3109/14653249.2010.523077

    Article  PubMed  CAS  Google Scholar 

  39. Spaggiari GM, Capobianco A, Abdelrazik H et al (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111:1327–1333. https://doi.org/10.1182/blood-2007-02-074997

    Article  PubMed  CAS  Google Scholar 

  40. Pradier A, Passweg J, Villard J, Kindler V (2011) Human bone marrow stromal cells and skin fibroblasts inhibit natural killer cell proliferation and cytotoxic activity. Cell Transplant 20:681–691. https://doi.org/10.3727/096368910X536545

    Article  PubMed  Google Scholar 

  41. Chatterjee D, Marquardt N, Tufa DM et al (2014) Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity. Cell Commun Signal 12:63. https://doi.org/10.1186/s12964-014-0063-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Zhao Z-G, Cao Z, Xu W et al (2012) Immune protection function of multipotent mesenchymal stromal cells: role of transforming growth factor-β1. Cancer Invest 30:646–656. https://doi.org/10.3109/07357907.2012.721038

    Article  PubMed  CAS  Google Scholar 

  43. Li Y, Qu Y, Wu Y et al (2011) Bone marrow mesenchymal stem cells reduce the antitumor activity of cytokine-induced killer/natural killer cells in K562 NOD/SCID mice. Ann Hematol 90:873–885. https://doi.org/10.1007/s00277-011-1156-9

    Article  PubMed  Google Scholar 

  44. Giuliani M, Oudrhiri N (2011) Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery. Blood 118:3254–3262. https://doi.org/10.1182/blood-2010-12-325324

    Article  PubMed  CAS  Google Scholar 

  45. Pazina T, Shemesh A, Brusilovsky M et al (2017) Regulation of the functions of natural cytotoxicity receptors by interactions with diverse ligands and alterations in splice variant expression. Front Immunol 8:369. https://doi.org/10.3389/fimmu.2017.00369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lebbink RJ, van den Berg MCW, de Ruiter T et al (2008) The soluble leukocyte-associated Ig-like receptor (LAIR)-2 antagonizes the collagen/LAIR-1 inhibitory immune interaction. J Immunol 180:1662–1669. https://doi.org/10.4049/jimmunol.180.3.1662

    Article  PubMed  CAS  Google Scholar 

  47. Fu Q, Man X, Yu M et al (2017) Human decidua mesenchymal stem cells regulate decidual natural killer cell function via interactions between collagen and leukocyte‑associated immunoglobulin‑like receptor 1. Mol Med Rep 16:2791–2798. https://doi.org/10.3892/mmr.2017.6921

    Article  PubMed  CAS  Google Scholar 

  48. Warren HS (1996) NK cell proliferation and inflammation. Immunol Cell Biol 74:473–480. https://doi.org/10.1038/icb.1996.78

    Article  PubMed  CAS  Google Scholar 

  49. Blanco B, Herrero-Sánchez MC, Rodríguez-Serrano C et al (2016) Immunomodulatory effects of bone marrow versus adipose tissue derived mesenchymal stromal cells on NK cells: implications in the transplantation setting. Eur J Haematol. https://doi.org/10.1111/ejh.12765

    Article  PubMed  Google Scholar 

  50. Perussia (1996) The cytokine profile of resting and activated NK cells. Methods 9:370–378

    Article  PubMed  CAS  Google Scholar 

  51. Thomas H, Jäger M, Mauel K et al. (2014) Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. https://doi.org/10.1155/2014/143463

  52. Chatterjee D, Marquardt N, Tufa DM et al (2014) Human umbilical cord-derived mesenchymal stem cells utilize activin-A to suppress interferon-γ production by natural killer cells. Front Immunol 5:662. https://doi.org/10.3389/fimmu.2014.00662

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822. https://doi.org/10.1182/blood-2004-04-1559

    Article  PubMed  CAS  Google Scholar 

  54. Noone C, Kihm A, English K et al (2013) IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev 22:3003–3014. https://doi.org/10.1089/scd.2013.0028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Almeida CR, Vasconcelos DP, Gonçalves RM, Barbosa MA (2012) Enhanced mesenchymal stromal cell recruitment via natural killer cells by incorporation of inflammatory signals in biomaterials. J R Soc Interface 9:261–271. https://doi.org/10.1098/rsif.2011.0357

    Article  PubMed  CAS  Google Scholar 

  56. Petri RM, Hackel A, Hahnel K et al (2017) Activated tissue-resident mesenchymal stromal cells regulate natural killer cell immune and tissue-regenerative function. Stem Cell Rep 280:12239–12245. https://doi.org/10.1016/j.stemcr.2017.06.020

    Article  CAS  Google Scholar 

  57. Cui R, Rekasi H, Hepner-Schefczyk M et al (2016) Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients. Stem Cell Res Ther 7:88. https://doi.org/10.1186/s13287-016-0353-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Krzewski K, Coligan JE (2012) Human NK cell lytic granules and regulation of their exocytosis. Front Immunol. https://doi.org/10.3389/fimmu.2012.00335

    Article  PubMed  PubMed Central  Google Scholar 

  59. Alter G, Malenfant JM, Altfeld M (2004) CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods 294:15–22. https://doi.org/10.1016/j.jim.2004.08.008

    Article  PubMed  CAS  Google Scholar 

  60. de Witte SFH, Merino AM, Franquesa M et al (2017) Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease. Stem Cell Res Ther 8:140. https://doi.org/10.1186/s13287-017-0590-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6:940–952. https://doi.org/10.1038/nri1983

    Article  PubMed  CAS  Google Scholar 

  62. Chen X, Song M, Zhang B, Zhang Y (2016) Reactive oxygen species regulate T cell immune response in the tumor microenvironment. Oxidative Med Cell Longev 2016:1–10. https://doi.org/10.1155/2016/1580967

    Article  CAS  Google Scholar 

  63. Padgett LE, Broniowska KA, Hansen PA et al (2013) The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis. Ann N Y Acad Sci 1281:16–35. https://doi.org/10.1111/j.1749-6632.2012.06826.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kaiserman D, Bird PI (2010) Control of granzymes by serpins. Cell Death Differ 17:586–595. https://doi.org/10.1038/cdd.2009.169

    Article  PubMed  CAS  Google Scholar 

  65. El Haddad N, Moore R, Heathcote D et al (2011) The novel role of SERPINB9 in cytotoxic protection of human mesenchymal stem cells. J Immunol 187:2252–2260. https://doi.org/10.4049/jimmunol.1003981

    Article  PubMed  Google Scholar 

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Acknowledgements

This project was supported by “Le Fonds National de la Recherche Scientifique, F.R.S.-FNRS” and the “Télévie”.

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  1. Mehdi Najar and Mohammad Fayyad-Kazan are co-first authors with equal contribution.

  2. Hussein Fayyad-Kazan and Laurence Lagneaux are senior co-authors.

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  1. Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium

    Mehdi Najar, Nathalie Meuleman, Dominique Bron & Laurence Lagneaux

  2. Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium

    Mohammad Fayyad-Kazan, Nathalie Meuleman & Dominique Bron

  3. Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon

    Hussein Fayyad-Kazan

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Najar, M., Fayyad-Kazan, M., Meuleman, N. et al. Immunological impact of Wharton’s Jelly mesenchymal stromal cells and natural killer cell co-culture. Mol Cell Biochem 447, 111–124 (2018). https://doi.org/10.1007/s11010-018-3297-9

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