Zinc improves the development of human CD34+ cell progenitors towards NK cells and increases the expression of GATA-3 transcription factor in young and old ages

Abstract

Aim of this study was to evaluate the effect of zinc on the kinetic of development of CD34+ cell progenitors towards NK cells in young and old ages. CD34+ cells were purified from peripheral blood of healthy subjects and cultured in medium supplemented with interleukin-15, interleukin-7, Flt 3 ligand, and stem cell factor. The number of cells developed in culture was significantly lower in old than in young subjects. CD34+ cells progressively lost CD34 antigen with a faster kinetics in old than in young donors. The percentage of primitive double positive CD34+CD133+ cells inside the purified CD34+ cells was greatly lower in old than in young subjects. These cells progressively decreased in cultures from young subjects whereas they remained at very low levels in old donors. Cells developed in culture acquired a NK phenotype mainly characterized by CD56+CD16 cells in young subjects and CD56CD16+ cells in old donors. These NK cells exerted a lower cytotoxic activity in old than in young subjects. The supplementation with zinc greatly increased the number of cells in culture and the percentage and the cytotoxic activity of NK cells both in young and old ages. In zinc supplemented cultures, a 3.6-fold and a 4.1-fold increased expression of GATA-3 transcription factor was observed in young and old donors, respectively. Our data demonstrate that zinc influences the proliferation and differentiation of CD34+ progenitors both in young and old ages.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Carayol G, Robin C, Bourhis JH, Bennaceur-Griscelli A, Chouaib S, Coulombel L, Caignard A (1998) NK cell differentiated from bone marrow, cord blood and peripheral blood stem cells exibit similar phenotype and functions. Eur J Immunol 28:1991–2002. doi:10.1002/(SICI)1521-4141(199806)28:06<1991::AID-IMMU1991>3.0.CO;2-7

    PubMed  Article  CAS  Google Scholar 

  2. Chidrawar SM, Khan N, Tracey Chan YL, Nayak L, Moss PAH (2006) Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing 3:10–18. doi:10.1186/1742-4933-3-10

    PubMed  Article  Google Scholar 

  3. Donnini A, Re F, Orlando F, Provinciali M (2007) Intrinsic and microenvironmental defects are involved in the age-related changes of Lin-c-kit + hematopoietic progenitor cells. Rejuvenation Res 10:459–472. doi:10.1089/rej.2006.0524

    PubMed  Article  CAS  Google Scholar 

  4. Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085. doi:10.1073/pnas.94.8.4080

    PubMed  Article  CAS  Google Scholar 

  5. Fabris N, Mocchegiani E (1995) Zinc, human diseases and ageing. Aging Clin Exp Res 7:77–93

    CAS  Google Scholar 

  6. Fabris N, Mocchegiani E, Provinciali M (1990) Zinc, immunity and aging. In: Goldstein AL (ed) Biochemical advances in aging. Plenum Press, New York, pp 271–281

    Google Scholar 

  7. Ferreira R, Ohneda K, Yamamoto M, Philipsen S (2005) GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol 25:1215–1227. doi:10.1128/MCB.25.4.1215-1227.2005

    PubMed  Article  CAS  Google Scholar 

  8. Fraker PJ, King LE, Lakko T, Vollmer TL (2000) The dynamic link between the integrity of the immune system and zinc status. J Nutr 130:1399S–1406S

    PubMed  CAS  Google Scholar 

  9. Fuchs E, Segre JA (2000) Stem cells: a new lease of life. Cell 100:143–155. doi:10.1016/S0092-8674(00)81691-8

    PubMed  Article  CAS  Google Scholar 

  10. Galy A, Travis MCD, Chen D, Chen B (1995) Natural Killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 3:459–473. doi:10.1016/1074-7613(95)90175-2

    PubMed  Article  CAS  Google Scholar 

  11. Globerson A (1999) Hematopoietic stem cells and aging. Exp Gerontol 34:137–146. doi:10.1016/S0531-5565(98)00069-2

    PubMed  Article  CAS  Google Scholar 

  12. Ko LJ, Engel JD (1993) DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol 13:4011–4022

    PubMed  CAS  Google Scholar 

  13. Krause DS (2002) Plasticity of marrow-derived stem cells. Gene Ther 9:754–758. doi:10.1038/sj.gt.3301760

    PubMed  Article  CAS  Google Scholar 

  14. Krishnaraj R (1997) Senescence and cytokines modulate the NK cell expression. Mech Ageing Dev 96:89–101. doi:10.1016/S0047-6374(97)00045-6

    PubMed  Article  CAS  Google Scholar 

  15. Martin DI, Orkin SH (1990) Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1. Genes Dev 4:1886–1898. doi:10.1101/gad.4.11.1886

    PubMed  Article  CAS  Google Scholar 

  16. Miltenyi S, Muller W, Weichel W, Radbruch A (1990) High gradient magnetic cell separation with MACS. Cytometry 11:231–238. doi:10.1002/cyto.990110203

    PubMed  Article  CAS  Google Scholar 

  17. Mocchegiani E, Marcellini F, Pawelec G (2004) Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic, and lifestyle implications for healthy ageing. Biogerontology 5:271–273. doi:10.1023/B:BGEN.0000038048.11766.64

    PubMed  Article  CAS  Google Scholar 

  18. Mocchegiani E, Muzzioli M, Cipriano C, Giacconi R (1998) Zinc, T-cell pathways, aging: role of metallothioneins. Mech Ageing Dev 106:183–204. doi:10.1016/S0047-6374(98)00115-8

    PubMed  Article  CAS  Google Scholar 

  19. Moresi R, Tesei S, Costarelli L, Viticchi C, Stecconi R, Bernardini G, Provinciali M (2005) Age- and gender-related alterations of the number and clonogenic capacity of circulating CD34+ progenitor cells. Biogerontology 6:185–192. doi:10.1007/s10522-005-7954-5

    PubMed  Article  CAS  Google Scholar 

  20. Mrozek E, Anderson P, Caligiuri M (1996) Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood 87:2632–2640

    PubMed  CAS  Google Scholar 

  21. Muench MO, Humeau L, Paek B, Ohkubo T, Lanier LL, Albanese CT, Barcena A (2000) Differential effects of interleukin-3, interleukin-7, interleukin-15, and granulocyte-macrophage colony-stimulating factor in the generation of natural killer and B cells from primitive human fetal liver progenitors. Exp Hematol 28:961–973. doi:10.1016/S0301-472X(00)00490-2

    PubMed  Article  CAS  Google Scholar 

  22. Muzzioli M, Stecconi R, Donnini A, Re F, Provinciali M (2007) Zinc improves the development of human CD34+ cell progenitors towards NK cells and induces the expression of GATA-3 transcription factor. Int J Biochem Cell Biol 39:955–965. doi:10.1016/j.biocel.2007.01.011

    PubMed  Article  CAS  Google Scholar 

  23. Orange JS, Ballas ZK (2006) Natural killer cells in human health and disease. Clin Immunol 118:1–10. doi:10.1016/j.clim.2005.10.011

    PubMed  Article  CAS  Google Scholar 

  24. Pavletich NP, Pabo CO (1991) Zinc finger-DNA recognition: crystal structure of a ZIF268-DNA complex at 2.1 A. Science 252:809–817. doi:10.1126/science.2028256

    PubMed  Article  CAS  Google Scholar 

  25. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    PubMed  Article  CAS  Google Scholar 

  26. Provinciali M, Di Stefano G, Fabris N (1992) Optimization of cytotoxic assay by target cell retention of the fluorescent dye carboxyfluorescein diacetate (CFDA) and comparison with conventional 51CR release assay. J Immunol Methods 155:19–24. doi:10.1016/0022-1759(92)90266-V

    PubMed  Article  CAS  Google Scholar 

  27. Provinciali M, Di Stefano G, Stronati S (1998) Flow cytometric analysis of CD3/TCR complex, zinc, and glucocorticoid-mediated regulation of apoptosis and cell cycle distribution in thymocytes from old mice. Cytometry 32:1–8. doi:10.1002/(SICI)1097-0320(19980501)32:1<1::AID-CYTO1>3.0.CO;2-Q

    PubMed  Article  CAS  Google Scholar 

  28. Provinciali M, Donnini A, Argentati K, Di Stasio G, Bartozzi B, Bernardini G (2002) Reactive oxygen species modulate Zn2+-induced apoptosis in cancer cells. Free Radic Biol Med 32:431–445. doi:10.1016/S0891-5849(01)00830-9

    PubMed  Article  CAS  Google Scholar 

  29. Puzanov I, Bennet M, Kumar V (1996) IL-15 can substitute for the marrow microenvironment in the differentiation of natural killer cells. J Immunol 157:4282–4285

    PubMed  CAS  Google Scholar 

  30. Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, Marcato A, Passeri G, Ortolani C, Forti E (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82:2767–2774

    PubMed  CAS  Google Scholar 

  31. Schwenger GTF, Mordvinov VA, Sanderson CJ (2005) Transcription factor GATA-3 is involved in repression of promoter activity of the human interleukin-4 gene. Biochemistry 70:1065–1069

    PubMed  CAS  Google Scholar 

  32. Sconocchia G, Fujiwara H, Rezvani K, Keyvanfar K, Ouriaghli FE, Grube M, Melenhorst J et al (2004) G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte. J Leukoc Biol 76:1214–1219. doi:10.1189/jlb.0504278

    PubMed  Article  CAS  Google Scholar 

  33. Sconocchia G, Provenzano M, Rezvani K, Li J, Melenhorst J, Hensel N, Barrett JA (2005) CD34+ cells cultured in stem cell factor and interleukin-2 generate CD56+ cells with antiproliferative effects on tumor cell lines. J Transl Med 3:15–19. doi:10.1186/1479-5876-3-15

    PubMed  Article  Google Scholar 

  34. Silva MR, Hoffman R, Srour EF, Ascensao J (1994) Generation of human natural killer cells from immature progenitors does not require marrow stromal cells. Blood 84:841–846

    PubMed  CAS  Google Scholar 

  35. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 95:503–510. doi:10.1038/ni1582

    Article  Google Scholar 

  36. Watt FM, Hogan BL (2000) Out of Eden: stem cells and their niches. Science 287:1427–1430. doi:10.1126/science.287.5457.1427

    PubMed  Article  CAS  Google Scholar 

  37. Weissman IL (2000) Stem cells: units of development, units of regeneration, and units in evolution. Cell 100:157–168. doi:10.1016/S0092-8674(00)81692-X

    PubMed  Article  CAS  Google Scholar 

  38. Wulf GG, Jackson KA, Goodell MA (2001) Somatic stem cell plasticity: current evidence and emerging concepts. Exp Hematol 29:1361–1370. doi:10.1016/S0301-472X(01)00752-4

    PubMed  Article  CAS  Google Scholar 

  39. Yu H, Fehniger TA, Fuchshuber P, Thiel KS, Vivier E, Carson WE, Caligiuri MA (1998) Flt3 ligand promotes the generation of a distinct CD34+ human natural killer cell progenitor that responds to interleukin-15. Blood 92:3647–3657

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mr. Giovanni Bernardini for performing flow cytometry.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mauro Provinciali.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Muzzioli, M., Stecconi, R., Moresi, R. et al. Zinc improves the development of human CD34+ cell progenitors towards NK cells and increases the expression of GATA-3 transcription factor in young and old ages. Biogerontology 10, 593–604 (2009). https://doi.org/10.1007/s10522-008-9201-3

Download citation

Keywords

  • Ageing
  • CD34 cell progenitors
  • Zinc
  • NK cells
  • Human
  • GATA-3