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, Francesco Di Virgilio

Research output: Contribution to journalArticle

Abstract

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 [PaRs]) are expressed on human hematopoietic stem calls (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 PaYRs 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.

Original languageEnglish
Pages (from-to)1662-1670
Number of pages9
JournalBlood
Volume104
Issue number6
DOIs
Publication statusPublished - Sep 15 2004

ASJC Scopus subject areas

  • Hematology

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