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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1662-1670. Prepublished online as a Blood First Edition Paper on May 25, 2004; DOI 10.1182/blood-2004-03-0834. This Article Full Text (PDF) All Versions of this Article: 2004-03-0834v1 104/6/1662    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lemoli, R. M Articles by Di Virgilio, F. Search for Related Content PubMed PubMed Citation Articles by Lemoli, R. M Articles by Di Virgilio, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 4, 2004 Accepted May 10, 2004 Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo Roberto M Lemoli*, Davide Ferrari, Miriam Fogli, Lara Rossi, Cinzia Pizzirani, Sylvia Forchap, Paola Chiozzi, Diletta Vaselli, Francesco Bertolini, Thomas Foutz, Michela Aluigi, Michele Baccarani, and Francesco Di Virgilio Institute of Hematology and Medical Oncology, 'L. & A. Seragnoli', University of Bologna, Bologna, Italy Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Ferrara, Italy Department of Hematology, European Institute of Oncology, Milan, Italy * Corresponding author; email: rmlemoli{at}med.unibo.it. Although extracellular nucleotides support a wide range of biological responses of mature blood cells, little is known on their effect on blood cell progenitor cells. In this study, we assessed whether receptors for extracellular nucleotides (P2 receptors, P2R) are expressed on human hematopoietic stem cells (HSC), and whether activation by their natural ligands, ATP and UTP, induces HSC proliferation in vitro and in vivo. Our results demonstrated that CD34+ HSC express functional P2XR and P2YR of several subtypes. Furthermore, stimulation of CD34+ cells with extracellular nucleotides caused a fast release of Ca2+ from intracellular stores and an increase in ion fluxes across the plasma membrane. Functionally, ATP and, to a higher extent, UTP acted as potent early-acting growth factors for HSC, in vitro, as they strongly enhanced the stimulatory activity of several cytokines on clonogenic CD34+ and lineage negative CD34- progenitors and expanded more primitive CD34+-derived long-term culture-initiating cells. Furthermore, xenogenic transplant studies showed that short-term pre-incubation with UTP significantly expanded the number of marrow repopulating HSC in nonobese diabetic/severe combined immunedeficiency mice. Our data suggest that extracellular nucleotides may provide a novel and powerful tool to modulate HSC functions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. J. Paredes-Gamero, C. M. M. P. Leon, R. Borojevic, M. E. M. Oshiro, and A. T. Ferreira Changes in Intracellular Ca2+ Levels Induced by Cytokines and P2 Agonists Differentially Modulate Proliferation or Commitment with Macrophage Differentiation in Murine Hematopoietic Cells J. Biol. Chem., November 14, 2008; 283(46): 31909 - 31919. [Abstract] [Full Text] [PDF] L. Rossi, R. Manfredini, F. Bertolini, D. Ferrari, M. Fogli, R. Zini, S. Salati, V. Salvestrini, S. Gulinelli, E. Adinolfi, et al. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration Blood, January 15, 2007; 109(2): 533 - 542. [Abstract] [Full Text] [PDF] G. Burnstock Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol. Rev., March 1, 2006; 58(1): 58 - 86. [Abstract] [Full Text] [PDF] S. K. Mishra, N. Braun, V. Shukla, M. Fullgrabe, C. Schomerus, H.-W. Korf, C. Gachet, Y. Ikehara, J. Sevigny, S. C. Robson, et al. Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation Development, February 15, 2006; 133(4): 675 - 684. [Abstract] [Full Text] [PDF] D. Ferrari, A. la Sala, E. Panther, J. Norgauer, F. Di Virgilio, and M. Idzko Activation of human eosinophils via P2 receptors: novel findings and future perspectives J. Leukoc. Biol., January 1, 2006; 79(1): 7 - 15. [Abstract] [Full Text] [PDF] T. Mandle, H. Einsele, M. Schaller, D. Neumann, W. Vogel, I. B. Autenrieth, and V. A. J. Kempf Infection of human CD34+ progenitor cells with Bartonella henselae results in intraerythrocytic presence of B henselae Blood, August 15, 2005; 106(4): 1215 - 1222. [Abstract] [Full Text] [PDF]

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