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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.
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HEMATOPOIESIS
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
From the Institute of Hematology and Medical Oncology "L. & A. Seràgnoli," University of Bologna, Bologna, Italy; Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrara, Italy; and Department of Hematology and Oncology, European Institute of Oncology, Milan, Italy.
Although extracellular nucleotides support a wide range of biologic responses of mature blood cells, little is known about their effect on blood cell progenitor cells. In this study, we assessed whether receptors for extracellular nucleotides (P2 receptors [P2Rs]) are expressed on human hematopoietic stem cells (HSCs), and whether activation by their natural ligands, adenosine triphosphate (ATP) and uridine triphosphate (UTP), induces HSC proliferation in vitro and in vivo. Our results demonstrated that CD34+ HSCs express functional P2XRs and P2YRs 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 HSCs, in vitro, because 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 transplantation studies showed that short-term preincubation with UTP significantly expanded the number of marrow-repopulating HSCs in nonobese diabetic/severe combined immunodeficiency mice. Our data suggest that extracellular nucleotides may provide a novel and powerful tool to modulate HSC functions. (Blood. 2004;104:1662-1670)
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