Skip to main content
Log in

High Level P2X7-Mediated Signaling Impairs Function of Hematopoietic Stem/Progenitor Cells

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Nucleotides, which bind to P2 receptors, have emerged as a family of mediators in intercellular communication. P2X7 is a member of the P2X family ligand-gated ion channels respond to extracellular ATP. High level expression of P2X7 was detected in leukemia samples, especially in relapsed cases. However, the role of P2X7 mediated signaling in hematopoietic stem/progenitor cells (HSPCs) as well as its potential role in leukemogenesis have not been established. In this study, the expression of P2X7 in hematopoietic cells in different lineages and stages was analyzed. Over-expression of P2X7 in HSPCs was carried out by retrovirus infection to study the impact on HSPCs. The results showed that low level expression of P2X7 was detected in HSPCs. Over-expression of P2X7 in HSPCs resulted in decreased colony forming ability in vitro and engraftment potential in vivo. These results suggested that high level purinergic signaling by P2X7 impaired function of HSPCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ratajczak, M. Z., & Suszynska, M. (2015). Emerging strategies to enhance homing and engraftment of hematopoietic stem cells. Stem Cell Reviews. doi:10.1007/s12015-015-9625-5.

    PubMed  Google Scholar 

  2. Idzko, M., Ferrari, D., & Eltzschig, H. K. (2014). Nucleotide signalling during inflammation. Nature, 509(7500), 310–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jacob, F., Perez, N. C., Bachert, C., & Van Crombruggen, K. (2013). Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal, 9(3), 285–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Coddou, C., Yan, Z., Obsil, T., Huidobro-Toro, J. P., & Stojilkovic, S. S. (2011). Activation and regulation of purinergic P2X receptor channels. Pharmacological Reviews, 63(3), 641–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bartlett, R., Stokes, L., & Sluyter, R. (2014). The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacological Reviews, 66(3), 638–675.

    Article  CAS  PubMed  Google Scholar 

  6. Sperlagh, B., & Illes, P. (2014). P2X7 receptor: an emerging target in central nervous system diseases. Trends in Pharmacological Sciences, 35(10), 537–547.

    Article  CAS  PubMed  Google Scholar 

  7. Rossi, L., Salvestrini, V., Ferrari, D., Di Virgilio, F., & Lemoli, R. M. (2012). The sixth sense: hematopoietic stem cells detect danger through purinergic signaling. Blood, 120(12), 2365–2375.

    Article  CAS  PubMed  Google Scholar 

  8. Sluyter, R. (2015). P2X and P2Y receptor signaling in red blood cells. Frontiers in Molecular Biosciences, 2, 60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Menzies, R. I., Unwin, R. J., & Bailey, M. A. (2015). Renal P2 receptors and hypertension. Acta Physiologica (Oxford, England), 213(1), 232–241.

    Article  CAS  Google Scholar 

  10. Eaves, C. J. (2015). Hematopoietic stem cells: concepts, definitions, and the new reality. Blood, 125(17), 2605–2613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hyman, M. C., Petrovic-Djergovic, D., Visovatti, S. H., et al. (2009). Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. The Journal of Clinical Investigation, 119(5), 1136–1149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Muller, T., Robaye, B., Vieira, R. P., et al. (2010). The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy, 65(12), 1545–1553.

    Article  CAS  PubMed  Google Scholar 

  13. Karim, Z. A., Vemana, H. P., Alshbool, F. Z., et al. (2015). Characterization of a novel function-blocking antibody targeted against the platelet P2Y1 receptor. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(3), 637–644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Burnstock, G. (2015). Blood cells: an historical account of the roles of purinergic signalling. Purinergic Signal, 11(4), 411–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Casati, A., Frascoli, M., Traggiai, E., Proietti, M., Schenk, U., & Grassi, F. (2011). Cell-autonomous regulation of hematopoietic stem cell cycling activity by ATP. Cell Death and Differentiation, 18(3), 396–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sak, K., Boeynaems, J. M., & Everaus, H. (2003). Involvement of P2Y receptors in the differentiation of haematopoietic cells. Journal of Leukocyte Biology, 73(4), 442–447.

    Article  CAS  PubMed  Google Scholar 

  17. Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L., & Weissman, I. L. (2001). Physiological migration of hematopoietic stem and progenitor cells. Science, 294(5548), 1933–1936.

    Article  CAS  PubMed  Google Scholar 

  18. Cho, J., Yusuf, R., Kook, S., et al. (2014). Purinergic P2Y(1)(4) receptor modulates stress-induced hematopoietic stem/progenitor cell senescence. The Journal of Clinical Investigation, 124(7), 3159–3171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Di Virgilio, F., & Vuerich, M. (2015). Purinergic signaling in the immune system. Autonomic Neuroscience, 191, 117–123.

    Article  PubMed  Google Scholar 

  20. Rissiek, B., Haag, F., Boyer, O., Koch-Nolte, F., & Adriouch, S. (2015). P2X7 on mouse T cells: one channel, many functions. Frontiers in Immunology, 6, 204.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pippel, A., Bessler, B., Klapperstuck, M., & Markwardt, F. (2015). Inhibition of antigen receptor-dependent Ca(2+) signals and NF-AT activation by P2X7 receptors in human B lymphocytes. Cell Calcium, 57(4), 275–289.

    Article  CAS  PubMed  Google Scholar 

  22. Dagvadorj, J., Shimada, K., Chen, S., et al. (2015). Lipopolysaccharide induces alveolar macrophage necrosis via CD14 and the P2X7 receptor leading to interleukin-1alpha release. Immunity, 42(4), 640–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Da, S. G., Sperotto, N. D., Borges, T. J., et al. (2013). P2X7 receptor is required for neutrophil accumulation in a mouse model of irritant contact dermatitis. Experimental Dermatology, 22(3), 184–188.

    Article  Google Scholar 

  24. Muller, T., Vieira, R. P., Grimm, M., et al. (2011). A potential role for P2X7R in allergic airway inflammation in mice and humans. American Journal of Respiratory Cell and Molecular Biology, 44(4), 456–464.

    Article  PubMed  Google Scholar 

  25. Hechler, B., & Gachet, C. (2015). Purinergic receptors in thrombosis and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(11), 2307–2315.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, X. J., Zheng, G. G., Ma, X. T., et al. (2004). Expression of P2X7 in human hematopoietic cell lines and leukemia patients. Leukemia Research, 28(12), 1313–1322.

    Article  CAS  PubMed  Google Scholar 

  27. Chong, J. H., Zheng, G. G., Zhu, X. F., et al. (2010). Abnormal expression of P2X family receptors in Chinese pediatric acute leukemias. Biochemical and Biophysical Research Communications, 391(1), 498–504.

    Article  CAS  PubMed  Google Scholar 

  28. Chong, J. H., Zheng, G. G., Ma, Y. Y., et al. (2010). The hyposensitive N187D P2X7 mutant promotes malignant progression in nude mice. The Journal of Biological Chemistry, 285(46), 36179–36187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Visvader, J. E., & Lindeman, G. J. (2012). Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 10(6), 717–728.

    Article  CAS  PubMed  Google Scholar 

  30. Konopleva, M. Y., & Jordan, C. T. (2011). Leukemia stem cells and microenvironment: biology and therapeutic targeting. Journal of Clinical Oncology, 29(5), 591–599.

    Article  PubMed  Google Scholar 

  31. Cheng, H., Hao, S., Liu, Y., et al. (2015). Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation. Blood, 126(11), 1302–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schulte, R., Wilson, N. K., Prick, J. C., et al. (2015). Index sorting resolves heterogeneous murine hematopoietic stem cell populations. Experimental Hematology, 43(9), 803–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen, Y., Yao, Y., Sumi, Y., et al. (2010). Purinergic signaling: a fundamental mechanism in neutrophil activation. Science Signaling, 3(125), a45.

    Article  Google Scholar 

  34. Onnheim, K., Christenson, K., Gabl, M., et al. (2014). A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide. Experimental Cell Research, 323(1), 209–217.

    Article  PubMed  Google Scholar 

  35. Vaughan, K. R., Stokes, L., Prince, L. R., et al. (2007). Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y11 receptor. The Journal of Immunology, 179(12), 8544–8553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stoffels, M., Zaal, R., Kok, N., van der Meer, J. W., Dinarello, C. A., & Simon, A. (2015). ATP-induced IL-1beta specific secretion: true under stringent conditions. Frontiers in Immunology, 6, 54.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Castrejon-Jimenez, N. S., Leyva-Paredes, K., Hernandez-Gonzalez, J. C., Luna-Herrera, J., & Garcia-Perez, B. E. (2015). The role of autophagy in bacterial infections. Bioscience Trends, 9(3), 149–159.

    Article  PubMed  Google Scholar 

  38. Omatsu, Y., & Nagasawa, T. (2015). The critical and specific transcriptional regulator of the microenvironmental niche for hematopoietic stem and progenitor cells. Current Opinion in Hematology, 22(4), 330–336.

    CAS  PubMed  Google Scholar 

  39. Lensch, M. W. (2012). An evolving model of hematopoietic stem cell functional identity. Stem Cell Reviews, 8(2), 551–560.

    Article  CAS  PubMed  Google Scholar 

  40. Vaidya, A., & Kale, V. (2015). Hematopoietic stem cells, their niche, and the concept of co-culture systems: a critical review. Journal of Stem Cells, 10(1), 13–31.

    PubMed  Google Scholar 

  41. Adrian, K., Bernhard, M. K., Breitinger, H. G., & Ogilvie, A. (2000). Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells. Biochimica et Biophysica Acta, 1492(1), 127–138.

    Article  CAS  PubMed  Google Scholar 

  42. Schepers, K., Campbell, T. B., & Passegue, E. (2015). Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell, 16(3), 254–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Weissman, I. L. (2015). Stem cells are units of natural selection for tissue formation, for germline development, and in cancer development. Proceedings of the National Academy of Sciences of the United States of America, 112(29), 8922–8928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, Y., Chen, H. X., Zhou, S. Y., et al. (2015). Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway. Molecular Cancer, 14, 56.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Gao, Y., Yang, P., Shen, H., et al. (2015). Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nature Communications, 6, 6328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sirin, O., Lukov, G. L., Mao, R., Conneely, O. M., & Goodell, M. A. (2010). The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nature Cell Biology, 12(12), 1213–1219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sluyter, R., & Stokes, L. (2011). Significance of P2X7 receptor variants to human health and disease. Recent Patents on DNA & Gene Sequences, 5(1), 41–54.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants 81170511, 81370634, 81570153 and 81300376 from the National Natural Science Foundation of China (NSFC); Grants 14JCQNJC10600 from Tianjin Natural Science Foundation; and Graduate Student Innovation Fund from Peking Union Medical College (10023-0710-1021). Z.GG. was a recipient of the New Century Excellent Talents in University (NCET-08-0329).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Guoguang Zheng.

Ethics declarations

Conflicts of Interest

No potential conflicts of interest were disclosed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, W., Yang, F., Wang, R. et al. High Level P2X7-Mediated Signaling Impairs Function of Hematopoietic Stem/Progenitor Cells. Stem Cell Rev and Rep 12, 305–314 (2016). https://doi.org/10.1007/s12015-016-9651-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-016-9651-y

Keywords

Navigation