Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo.
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.
Lemoli
Roberto M
RM
Institute of Hematology and Medical Oncology L. & A. Seràgnoli, University of Bologna, Italy. rmlemoli@med.unibo.it
Ferrari
Davide
D
Fogli
Miriam
M
Rossi
Lara
L
Pizzirani
Cinzia
C
Forchap
Sylvia
S
Chiozzi
Paola
P
Vaselli
Diletta
D
Bertolini
Francesco
F
Foutz
Thomas
T
Aluigi
Michela
M
Baccarani
Michele
M
Di Virgilio
Francesco
F
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
D018952:Antigens, CD34; D003115:Colony-Stimulating Factors; D017077:Culture Media, Conditioned; D009711:Nucleotides; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D014544:Uridine Triphosphate