title: Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo.
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 [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 Ca(2+) 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.
authors.affiliation: Institute of Hematology and Medical Oncology L. & A. Seràgnoli, University of Bologna, Italy. rmlemoli@med.unibo.it
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lemoli
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.forename: Miriam
authors.initials: M
authors.lastname: Fogli
authors.forename: Lara
authors.initials: L
authors.lastname: Rossi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Pizzirani
authors.forename: Sylvia
authors.initials: S
authors.lastname: Forchap
authors.forename: Paola
authors.initials: P
authors.lastname: Chiozzi
authors.forename: Diletta
authors.initials: D
authors.lastname: Vaselli
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Thomas
authors.initials: T
authors.lastname: Foutz
authors.forename: Michela
authors.initials: M
authors.lastname: Aluigi
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009711:Nucleotides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000276:immunology; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D003115:Colony-Stimulating Factors; D017077:Culture Media, Conditioned; D009711:Nucleotides; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D014544:Uridine Triphosphate