Advertisement

Reciprocal immuno-biological alterations occur during the co-culture of natural killer cells and adipose tissue-derived mesenchymal stromal cells

  • Mehdi Najar
  • Mohammad Fayyad-KazanEmail author
  • Makram Merimi
  • Nathalie Meuleman
  • Dominique Bron
  • Hussein Fayyad-Kazan
  • Laurence Lagneaux
Original Article

Abstract

Due to their immune-therapeutic value, adipose tissue-derived mesenchymal stromal cells (AT-MSCs) require a better characterization of their interplay with natural killer (NK) cells known to contribute to the graft-versus-leukemia effects. When cultivated together, AT-MSCs showed cellular cytotoxicity and were therefore killed by NK cells in an activating-cytokine dependent manner. In the presence of AT-MSCs, both ligands and receptors known to drive NK cell interactions were significantly altered. During this co-culture, the proliferation of NK cells was slightly reduced, while their IFN-γ and TNF-α secretion was significantly increased. NK cells displayed sustained degranulation accompanied by increased discharge of their cytolytic granules (perforin, granzymes A and B). On the other hand, activated NK cells reduced the expression of serpins C1 and B9 in AT-MSCs. Collectively, reciprocal immuno-biological alterations occur during the co-culture of NK cells and AT-MSCs. Understanding these changes will increase the safety and efficacy of cell-based immuno-oncotherapy.

Keywords

AT-MSCs NK cells Immunomodulation Cell crosstalk 

Abbreviations

AT

Adipose tissue

TNF

Tumor necrosis factor

GVL

Graft-versus-leukemia

GVH

Graft-versus-host

IFN

Interferon

MSCs

Mesenchymal stromal cells

NK

Natural killer

PBMCs

Peripheral blood mononuclear cells

ROS

Reactive oxygen species

Notes

Acknowledgements

We thank Karlien Pieters for her technical assistance.

Funding

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

Compliance with ethical standards

Conflicts of interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the “Institut Jules Bordet” (Belgium) and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. Amorin B, Alegretti AP, Valim V, Pezzi A, Laureano AM, da Silva MAL, et al (2014) Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum Cell 27:137–150. http://www.ncbi.nlm.nih.gov/pubmed/24903975. Accessed 8 Jan 2018
  2. Auletta JJ, Eid SK, Wuttisarnwattana P, Silva I, Metheny L, Keller MD 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 33:601–614CrossRefGoogle Scholar
  3. Blanc KL, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, Ringdén O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet (London, England) 363:1439–1441CrossRefGoogle Scholar
  4. Blanco B, Herrero-Sánchez MC, Rodríguez-Serrano C, García-Martínez ML, Blanco JF, Muntión S 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 97:528–537CrossRefGoogle Scholar
  5. Bose K (2015) Proteases in apoptosis: pathways, protocols and translational advances, 1st edn. SpringerGoogle Scholar
  6. Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL et al (2013) 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 15:641–648. http://www.ncbi.nlm.nih.gov/pubmed/23570660. Accessed 8 Jan 2018
  7. Busser H, Bruyn C De, Urbain F, Najar M, Pieters K, Raicevic G et al (2014) Isolation of adipose-derived stromal cells without enzymatic treatment: expansion, phenotypical, and functional characterization. Stem Cells Dev 23:2390–2400CrossRefGoogle Scholar
  8. Chuang S-Y, Yang C-H, Chou C-C, Chiang Y-P, Chuang T-H, Hsu L-C (2013) TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation. Proc Natl Acad Sci USA 110:16079–16084CrossRefGoogle Scholar
  9. Ciuffi S, Zonefrati R, Brandi ML (2017) Adipose stem cells for bone tissue repair. Clin Cases Miner Bone Metab 14:217. http://www.ncbi.nlm.nih.gov/pubmed/29263737. Accessed 8 Jan 2018
  10. Crop MJ, Korevaar SS, de Kuiper R, Ijzermans JNM, van Besouw NM, Baan CC et al (2011) Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant 20:1547–1559CrossRefGoogle Scholar
  11. DelaRosa O, Sánchez-Correa B, Morgado S, Ramírez C, del Río B, Menta R 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 21:1333–1343CrossRefGoogle Scholar
  12. Fang B, Song Y, Zhao RC, Han Q, Lin Q (2007) Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc 39:1710–1713CrossRefGoogle Scholar
  13. Freytes DO, Kang JW, Marcos-Campos I, Vunjak-Novakovic G (2013) Macrophages modulate the viability and growth of human mesenchymal stem cells. J Cell Biochem 114:220–229CrossRefGoogle Scholar
  14. Giuliani M, Bennaceur-Griscelli A, Nanbakhsh A, Oudrhiri N, Chouaib S, Azzarone B et al (2014) TLR ligands stimulation protects MSC from NK killing. Stem Cells 32:290–300CrossRefGoogle Scholar
  15. Hoogduijn MJ, Roemeling-van Rhijn M, Korevaar SS, Engela AU, Weimar W, Baan CC (2011) Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies. Hum Gene Ther 22:1587–1591CrossRefGoogle Scholar
  16. Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95–109. http://www.ncbi.nlm.nih.gov/pubmed/11900986. Accessed 24 Jan 2018
  17. Jewett A, Arasteh A, Tseng HC, Behel A, Arasteh H, Yang W et al (2010) Strategies to rescue Mesenchymal Stem Cells (MSCs) and Dental Pulp Stem Cells (DPSCs) from NK cell mediated cytotoxicity. PLoS ONE 5:1–14CrossRefGoogle Scholar
  18. Kaiserman D, Bird PI (2010) Control of granzymes by serpins. Cell Death Differ 17:586–595CrossRefGoogle Scholar
  19. Lu Y, Waller EK (2009) Dichotomous role of interferon-γ in allogeneic bone marrow transplant. Biol Blood Marrow Transplant 15:1347–1353. http://www.ncbi.nlm.nih.gov/pubmed/19822293. Accessed 24 Jan 2018
  20. Lupatov AY, Kim YS, Bystrykh OA, Vakhrushev IV, Pavlovich SV, Yarygin KN, Sukhikh GT (2017) Effect of fibroblast-like cells of mesenchymal origin of cytotoxic activity of lymphocytes against NK-sensitive target cells. Bull Exp Biol Med 162:552–557CrossRefGoogle Scholar
  21. Menard C, Pacelli L, Bassi G, Dulong J, Bifari F, Bezier I et al (2013) Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls. Stem Cells Dev 22:1789–1801. http://www.ncbi.nlm.nih.gov/pubmed/23339531. Accessed 24 Jan 2018
  22. Najar M, Rouas R, Raicevic G, Boufker HI, Lewalle P, Meuleman N 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 11:570–583CrossRefGoogle Scholar
  23. Najar M, Raicevic G, Fayyad-Kazan H, Bruyn C De, Bron D, Toungouz M, Lagneaux L (2013) Impact of different mesenchymal stromal cell types on T-cell activation, proliferation and migration. Int Immunopharmacol 15:693–702CrossRefGoogle Scholar
  24. Najar M, Krayem M, Meuleman N, Bron D, Hélène B, Lagneaux L (2017) Immunohematology mesenchymal stromal cell-based therapy. Appl Immunohistochem Mol Morphol 1. http://www.ncbi.nlm.nih.gov/pubmed/29271793. Accessed 8 Jan 2018
  25. Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L (2018a) Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J Cell Commun Signal 12:673–688CrossRefGoogle Scholar
  26. Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L (2018b) Immunomodulatory effects of foreskin mesenchymal stromal cells on natural killer cells. J Cell Physiol 233:5243–5254CrossRefGoogle Scholar
  27. Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L (2018c) Immunological impact of Wharton’s Jelly mesenchymal stromal cells and natural killer cell co-culture. Mol Cell Biochem. http://www.ncbi.nlm.nih.gov/pubmed/29380244. Accessed 19 Feb 2018
  28. Noone C, Kihm A, English K, O’Dea S, Mahon BP (2013) IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev 22:3003–3014CrossRefGoogle Scholar
  29. Poggi A, Zocchi MR (2014) NK cell autoreactivity and autoimmune diseases. Front Immunol 5:27Google Scholar
  30. Qi K, Li N, Zhang Z, Melino G (2017) Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response. Cell Immunol. http://linkinghub.elsevier.com/retrieve/pii/S0008874917302198. Accessed 8 Jan 2018
  31. Ribeiro A, Laranjeira P, Mendes S, Velada I, Leite C, Andrade P 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 4:125–141CrossRefGoogle Scholar
  32. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24:74–85CrossRefGoogle Scholar
  33. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L (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 107:1484–1490CrossRefGoogle Scholar
  34. Thomas H, Jäger M, Mauel K, Brandau S, Lask S, Flohé SB (2014) Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm 2014:1–11. http://www.ncbi.nlm.nih.gov/pubmed/24876666. Accessed 15 Jan 2018
  35. Tseng H-C, Arasteh A, Paranjpe A, Teruel A, Yang W, Behel A et al (2010) Increased lysis of stem cells but not their differentiated cells by natural killer cells; de-differentiation or reprogramming activates NK cells. PLoS ONE 5:e11590CrossRefGoogle Scholar
  36. Valencic E, Loganes C, Cesana S, Piscianz E, Gaipa G, Biagi E, Tommasini A (2014) Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media. Stem Cell Res Ther 5:3CrossRefGoogle Scholar
  37. 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. http://www.ncbi.nlm.nih.gov/pubmed/24319201. Accessed 3 Aug 2017
  38. Wang R, Jaw JJ, Stutzman NC, Zou Z, Sun PD (2012) Natural killer cell-produced IFN-γ and TNF-α induce target cell cytolysis through up-regulation of ICAM-1. J Leukoc Biol 91:299–309. http://www.ncbi.nlm.nih.gov/pubmed/22045868. Accessed 24 January 2018
  39. Waters JP, Pober JS, Bradley JR (2013) Tumour necrosis factor and cancer. J Pathol 230:241–248. http://www.ncbi.nlm.nih.gov/pubmed/23460481. Accessed 24 Jan 2018
  40. Watzl C, Urlaub D, Fasbender F, Claus M (2014) Natural killer cell regulation—beyond the receptors. F1000Prime Rep 6: 87. http://www.ncbi.nlm.nih.gov/pubmed/25374665. Accessed 8 Jan 2018
  41. Yang Y-G, Wang H, Asavaroengchai W, Dey BR (2005) Role of interferon-gamma in GVHD and GVL. Cell Mol Immunol 2:323–329. http://www.ncbi.nlm.nih.gov/pubmed/16368058. Accessed 24 Jan 2018

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Mehdi Najar
    • 1
    • 2
  • Mohammad Fayyad-Kazan
    • 3
  • Makram Merimi
    • 3
    • 4
  • Nathalie Meuleman
    • 1
    • 3
  • Dominique Bron
    • 1
    • 3
  • Hussein Fayyad-Kazan
    • 5
  • Laurence Lagneaux
    • 1
  1. 1.Laboratory of Clinical Cell Therapy, Institut Jules BordetUniversité Libre de Bruxelles (ULB)BrusselsBelgium
  2. 2.Osteoarthritis Research UnitUniversity of Montreal Hospital Research Center (CRCHUM)MontrealCanada
  3. 3.Hematology Department, Institut Jules BordetUniversité Libre de BruxellesBrusselsBelgium
  4. 4.Laboratory of Physiology, Genetics and Ethnopharmacology, Faculty of SciencesUniversity Mohammed PremierOujdaMorocco
  5. 5.Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences ILebanese UniversityHadathLebanon

Personalised recommendations