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:

Stem Cells

Interferon-γ-induced neuronal differentiation of human umbilical cord blood-derived progenitors

Leukemia volume 23, pages 1790–1800 (2009)Cite this article

Abstract

Human umbilical cord blood (HUCB) provides a source of progenitors for cell therapy. We isolated and characterized an HUCB-derived population of progenitors (HUCBNP), differentiated toward neuronal phenotype by human neuroblastoma-conditioning medium (CM) and nerve growth factor (NGF), which have been found to confer neuroprotection toward hypoxia-mediated neuronal injury. This study investigated whether interferon-γ (IFN-γ) contributes to HUCBNP differentiation. IFN-γ was detected in the CM used for the induction of differentiation of HUCBNP and a neutralizing antibody of IFN-γ significantly inhibited either IFN-γ or CM-induced differentiation. Transcriptome analysis of CM-differentiated HUCBNP, identified 86 genes as highly upregulated, among them 25 were IFN-induced (such as 2′,5′-oligoadenylate synthetase 1 and 2, IFN-induced protein and transmembrane proteins, STAT1 (IFN-γ-receptor signal transducer and activator of transcription) and chemokine C-X-C motif ligand 5). Treatment of HUCBNP with human recombinant IFN-γ, inhibited cell proliferation in a dose-dependent manner. IFN-γ (1–100 ng/ml) enhanced neuronal differentiation, expressed by neurite outgrowths and increased expression of the neuronal markers β-tubulin III, microtubule-associated protein 2, neuronal nuclei, neurofilament M and neuronal-specific enolase. IFN-γ additively cooperated with NGF to induce the differentiation of HUCBNP. These data indicate that IFN-γ promotes neuronal differentiation of HUCB-derived progenitors, proposing its use in future protocols towards cell therapy.

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
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Harris DT, Badowski M, Ahmad N, Gaballa MA . The potential of cord blood stem cells for use in regenerative medicine. Expert Opin Biol Ther 2007; 7: 1311–1322.

    Article  CAS  Google Scholar 

  2. Cohen Y, Nagler A . Umbilical cord blood transplantation-how, when and for whom? Blood Rev 2004; 18: 167–179.

    Article  Google Scholar 

  3. Kamolz LP, Kolbus A, Wick N, Mazal PR, Eisenbock B, Burjak S et al. Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions. Burns 2006; 32: 9–16.

    Article  Google Scholar 

  4. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104: 2752–2760.

    Article  CAS  Google Scholar 

  5. Nunes VA, Cavaçana N, Canovas M, Strauss BE, Zatz M . Stem cells from umbilical cord blood differentiate into myotubes and express dystrophin in vitro only after exposure to in vivo muscle environment. Biol Cell 2007; 99: 185–196.

    Article  CAS  Google Scholar 

  6. Arien-Zakay H, Nagler A, Galski H, Lazarovici P . Neuronal conditioning medium and nerve growth factor induce neuronal differentiation of collagen-adherent progenitors derived from human umbilical cord blood. J Mol Neurosci 2007; 32: 179–191.

    Article  CAS  Google Scholar 

  7. McGuckin C, Jurga M, Ali H, Strbad M, Forraz N . Culture of embryonic-like stem cells from human umbilical cord blood and onward differentiation to neural cells in vitro. Nat Protoc 2008; 3: 1046–1055.

    Article  CAS  Google Scholar 

  8. Jinquan T, Quan S, Jacobi HH, Jing C, Millner A, Jensen B et al. CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma-inducible protein 10 and monokine induced by interferon gamma. Blood 2000; 96: 1230–1238.

    CAS  PubMed  Google Scholar 

  9. Arien-Zakay H, Lecht S, Bercu MM, Tabakman R, Kohen R, Galski H et al. Neuroprotection by cord blood neural progenitors involves antioxidants, neurotrophic and angiogenic factors. Exp Neurol 2009; 216: 83–94.

    Article  CAS  Google Scholar 

  10. Shearer WT, Kline MW, Abramson SL, Fenton T, Starr SE, Douglas SD . Recombinant human gamma interferon in human immunodeficiency virus-infected children: safety, CD4(+)-lymphocyte count, viral load, and neutrophil function (AIDS Clinical Trials Group Protocol 211). Clin Diagn Lab Immunol 1999; 6: 311–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Wald O, Weiss ID, Wald H, Shoham H, Bar-Shavit Y, Beider K et al. IFN-gamma acts on T cells to induce NK cell mobilization and accumulation in target organs. J Immunol 2006; 176: 4716–4729.

    Article  CAS  Google Scholar 

  12. Dafny N, Yang PB . Interferon and the central nervous system. Eur J Pharmacol 2005; 523: 1–15.

    Article  CAS  Google Scholar 

  13. Gaviria JM . Clinical use of recombinant human interferon gamma. www.uptodate.com, 2008.

  14. Improta T, Salvatore AM, Di Luzio A, Romeo G, Coccia EM, Calissano P . IFN-gamma facilitates NGF-induced neuronal differentiation in PC12 cells. Exp Cell Res 1988; 179: 1–9.

    Article  CAS  Google Scholar 

  15. Cho SG, Yi SY, Yoo YS . IFNgamma and TNFalpha synergistically induce neurite outgrowth on PC12 cells. Neurosci Lett 2005; 378: 49–54.

    Article  CAS  Google Scholar 

  16. Barish ME, Mansdorf NB, Raissdana SS . Gamma-interferon promotes differentiation of cultured cortical and hippocampal neurons. Dev Biol 1991; 144: 412–423.

    Article  CAS  Google Scholar 

  17. Wong G, Goldshmit Y, Turnley AM . Interferon-gamma but not TNF alpha promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp Neurol 2004; 187: 171–177.

    Article  CAS  Google Scholar 

  18. Baron R, Nemirovsky A, Harpaz I, Cohen H, Owens T, Monsonego A . IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease. FASEB J 2008; 22: 2843–2852.

    Article  CAS  Google Scholar 

  19. Katzir I, Shani J, Regev K, Shabashov D, Lazarovici P . A quantitative bioassay for nerve growth factor, using PC12 clones expressing different levels of trkA receptors. J Mol Neurosci 2002; 18: 251–264.

    Article  CAS  Google Scholar 

  20. Tavor S, Eisenbach M, Jacob-Hirsch J, Golan T, Petit I, Benzion K . et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia 2008; 22: 2151–2158.

    Article  CAS  Google Scholar 

  21. Margalit O, Somech R, Amariglio N, Rechavi G . Microarray-based gene expression profiling of hematologic malignancies: basic concepts and clinical applications. Blood Rev 2005; 19: 223–234.

    Article  CAS  Google Scholar 

  22. Hooker A, James D . The glycosylation heterogeneity of recombinant human IFN-gamma. J Interferon Cytokine Res 1998; 18: 287–295.

    Article  CAS  Google Scholar 

  23. Der SD, Zhou A, Williams BR, Silverman RH . Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 1998; 95: 15623–15628.

    Article  CAS  Google Scholar 

  24. Indraccolo S, Pfeffer U, Minuzzo S, Esposito G, Roni V, Mandruzzato S et al. Identification of genes selectively regulated by IFNs in endothelial cells. J Immunol 2007; 178: 1122–1135.

    Article  CAS  Google Scholar 

  25. Uwabe K, Matsumoto M, Nagata K . Monokine induced by interferon-gamma acts as a neurotrophic factor on PC12 cells and rat primary sympathetic neurons. J Biol Chem 2005; 280: 34268–34277.

    Article  CAS  Google Scholar 

  26. Lazarovici P, Marcinkiewicz C, Lelkes PI . Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF)-implications in drug development. Curr Pharm Des 2006; 12: 2609–2622.

    Article  CAS  Google Scholar 

  27. Song JH, Wang CX, Song DK, Wang P, Shuaib A, Hao C . Interferon gamma induces neurite outgrowth by up-regulation of p35 neuron-specific cyclin-dependent kinase 5 activator via activation of ERK1/2 pathway. J Biol Chem 2005; 280: 12896–12901.

    Article  CAS  Google Scholar 

  28. Kim SJ, Son TG, Kim K, Park HR, Mattson MP, Lee J . Interferon-gamma promotes differentiation of neural progenitor cells via the JNK pathway. Neurochem Res 2007; 32: 1399–1406.

    Article  CAS  Google Scholar 

  29. Lendahl U, Zimmerman LB, McKay RD . CNS stem cells express a new class of intermediate filament protein. Cell 1990; 60: 585–595.

    Article  CAS  Google Scholar 

  30. Ridge J, Terle DA, Dragunsky E, Levenbook I . Effects of gamma-IFN and NGF on subpopulations in a human neuroblastoma cell line: flow cytometric and morphological analysis. In Vitro Cell Dev Biol Anim 1996; 32: 238–248.

    Article  CAS  Google Scholar 

  31. Tekautz TM, Zhu K, Grenet J, Kaushal D, Kidd VJ, Lahti JM . Evaluation of IFN-gamma effects on apoptosis and gene expression in neuroblastoma—preclinical studies. Biochim Biophys Acta 2006; 1763: 1000–1010.

    Article  CAS  Google Scholar 

  32. De Ambrosis A, Casciano I, Croce M, Pagnan G, Radic L, Banelli B et al. An interferon-sensitive response element is involved in constitutive caspase-8 gene expression in neuroblastoma cells. Int J Cancer 2007; 120: 39–47.

    Article  CAS  Google Scholar 

  33. Corrias MV, Gribaudo G, Guarnaccia F, Ponzoni M . Induction of 2.5 OAS gene expression and activity is not sufficient for IFN-gamma-induced neuroblastoma cell differentiation. Int J Cancer 1995; 62: 223–229.

    Article  CAS  Google Scholar 

  34. Rozzo C, Chiesa V, Ponzoni M . Integrin up-regulation as marker of neuroblastoma cell differentiation: correlation with neurite extension. Cell Death Differ 1997; 4: 713–724.

    Article  CAS  Google Scholar 

  35. Vasaturo F, Modesti A, Scarpa S . Interferon gamma modifies fibronectin and laminin synthesis in human neuroblastoma cell lines. Int J Oncol 1998; 12: 895–898.

    CAS  PubMed  Google Scholar 

  36. Cetinkaya C, Hultquist A, Su Y, Wu S, Bahram F, Påhlman S et al. Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells. Mol Cancer Ther 2007; 6: 2634–2641.

    Article  CAS  Google Scholar 

  37. Mousa A, Seiger A, Kjaeldgaard A, Bakhiet M . Human first trimester forebrain cells express genes for inflammatory and anti-inflammatory cytokines. Cytokine 1999; 11: 55–60.

    Article  CAS  Google Scholar 

  38. Jonakait GM, Wei R, Sheng ZL, Hart RP, Ni L . Interferon-gamma promotes cholinergic differentiation of embryonic septal nuclei and adjacent basal forebrain. Neuron 1994; 12: 1149–1159.

    Article  CAS  Google Scholar 

  39. Plioplys AV . Expression of the 210 kDa neurofilament subunit in cultured central nervous system from normal and trisomy 16 mice: regulation by interferon. J Neurol Sci 1988; 85: 209–222.

    Article  CAS  Google Scholar 

  40. Ponzoni M, Casalaro A, Lanciotti M, Montaldo PG, Cornaglia-Ferraris P . The combination of gamma-interferon and tumor necrosis factor causes a rapid and extensive differentiation of human neuroblastoma cells. Cancer Res 1992; 52: 931–939.

    CAS  PubMed  Google Scholar 

  41. Vaudry D, Stork PJ, Lazarovici P, Eiden LE . Signaling pathways for PC12 cell differentiation: making the right connections. Science 2002; 296: 1648–1649.

    Article  CAS  Google Scholar 

  42. Wu YY, Bradshaw RA . Induction of neurite outgrowth by interleukin-6 is accompanied by activation of Stat3 signaling pathway in a variant PC12 cell (E2) line. J Biol Chem 1996; 271: 13023–13032.

    Article  CAS  Google Scholar 

  43. Parish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, Horne MK . The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice. J Neurosci 2002; 22: 8034–8041.

    Article  CAS  Google Scholar 

  44. Neuhoff S, Moers J, Rieks M, Grunwald T, Jensen A, Dermietzel R et al. Proliferation, differentiation, and cytokine secretion of human umbilical cord blood-derived mononuclear cells in vitro. Exp Hematol 2007; 35: 1119–1131.

    Article  CAS  Google Scholar 

  45. El-Badri NS, Hakki A, Saporta S, Liang X, Madhusodanan S, Willing AE et al. Cord blood mesenchymal stem cells: potential use in neurological disorders. Stem Cells Dev 2006; 15: 497–506.

    Article  CAS  Google Scholar 

  46. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 200: 123–135.

    Article  Google Scholar 

  47. Domanska-Janik K, Buzanska L, Lukomska B . A novel, neural potential of non-hematopoietic human umbilical cord blood stem cells. Int J Dev Biol 2008; 52: 237–248.

    Article  Google Scholar 

  48. Goldstein G, Toren A, Nagler A . Transplantation and other uses of human umbilical cord blood and stem cells. Curr Pharm Des 2007; 13: 1363–1373.

    Article  CAS  Google Scholar 

  49. Nan Z, Grande A, Sanberg CD, Sanberg PR, Low WC . Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann N Y Acad Sci 2005; 1049: 84–96.

    Article  Google Scholar 

  50. Chen SH, Chang FM, Tsai YC, Huang KF, Lin CL, Lin MT . Infusion of human umbilical cord blood cells protect against cerebral ischemia and damage during heatstroke in the rat. Exp Neurol 2006; 199: 67–76.

    Article  CAS  Google Scholar 

  51. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 2001; 32: 2682–2688.

    Article  CAS  Google Scholar 

  52. Lu D, Sanberg PR, Mahmood A, Li Y, Wang L, Sanchez-Ramos J et al. Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplant 2002; 11: 275–281.

    Article  Google Scholar 

  53. Chen CT, Foo NH, Liu WS, Chen SH . Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms. Pediatr Neonatol 2008; 49: 77–83.

    Article  Google Scholar 

  54. Stoll G, Jander S, Schroeter M . Cytokines in CNS disorders: neurotoxicity versus neuroprotection. J Neural Transm Suppl 2000; 59: 81–89.

    CAS  PubMed  Google Scholar 

  55. Mattson MP, Scheff SW . Endogenous neuroprotection factors and traumatic brain injury: mechanisms of action and implications for therapy. J Neurotrauma 1994; 11: 3–33.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Mrs Jasmine Jacob-Hirsch for the technical help with functional genomics. PL is affiliated with and supported in part by David R Bloom Center for Pharmacy and the Dr Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.

Author information

Author notes

  1. H Arien-Zakay: This study is part of a PhD thesis to be submitted to The Hebrew University of Jerusalem by HAZ

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    H Arien-Zakay, S Lecht, M M Bercu, H Galski & P Lazarovici

  2. The Sheba Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    N Amariglio & G Rechavi

  3. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    G Rechavi & A Nagler

  4. Division of Hematology and Bone Marrow Transplantation and Cord Blood Bank, Laboratory of Molecular Immunobiology, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    H Galski & A Nagler

Authors
  1. H Arien-Zakay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Lecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M M Bercu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Amariglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Rechavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Galski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Lazarovici
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Lazarovici.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arien-Zakay, H., Lecht, S., Bercu, M. et al. Interferon-γ-induced neuronal differentiation of human umbilical cord blood-derived progenitors. Leukemia 23, 1790–1800 (2009). https://doi.org/10.1038/leu.2009.106

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.106

Keywords

This article is cited by

Search

Advanced search

Quick links