Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo

Abstract

IntroductionDuring the last few years the biologic activity of extracellular nucleotides has been the focus of increasing attention. Responses to extracellular adenosine triphosphate (ATP) or uridine triphosphate (UTP) as different as cell proliferation, differentiation, chemotaxis, cytokine secretion, release of lysosomal constituents, generation of reactive oxygen or nitrogen species, and cell death have been reported by different groups. [1][2][3][4][5][6][7][8][9] The effects of extracellular nucleotides are mediated by specific plasma membrane receptors, which are classified into 2 families: metabotropic P2Y receptors (P2YRs) 10 and ionotropic P2X receptors (P2XRs). [11][12][13] P2YRs are typical G protein-coupled receptors with 7 transmembrane domains. Eight P2YRs have been cloned so far. Signal transduction occurs via activation of phospholipase C or stimulation/ inhibition of adenylate cyclase. ATP is an agonist at all P2Y subtypes, with the exception of P2Y 12 and P2Y 14 , where adenosine diphosphate (ADP) and uridine diphosphate (UDP)-glucose are the preferred agonists, respectively, and ATP is either ineffective or an antagonist. UTP is a better agonist than ATP at P2Y 4 and P2Y 6 , whereas at P2Y 2 ATP and UTP are equipotent. P2XRs are multimeric plasma membrane ion channels directly gated by ATP that mediate fast permeability changes to monovalent and divalent cations (Na ϩ , K ϩ , and Ca 2ϩ ). Seven P2X subunits have been cloned so far. P2Rs are widely expressed on mature blood cells. [14][15][16][17][18][19][20] Moreover, the expression and function of the P2X 7 R on B-cell chronic lymphocytic leukemia (B-CLL) cells correlate with the severity of the disease, and targeting of such receptors has been proposed as a novel form of treatment for chronic leukemia. 21 No information is currently available on the expression and function of P2Rs on human hematopoietic stem cells (HSCs). HSCs are identified by the expression of the CD34 antigen, a cell membrane phosphoglycoprotein present on human bone marrow (BM), peripheral blood (PB), and cord blood progenitors. 22 Animal models 23 and clinical transplantation studies 24 using highly enriched cell populations have demonstrated the capacity of CD34 ϩ cells to behave as true stem cells because they engraft lethally irradiated allogeneic hosts. Moreover, retrovirally marked autologous CD34 ϩ grafts sustain long-term hematopoiesis. 25 Recent studies have challenged the dogma that all HSCs express the CD34 antigen. [26][27][28][29][30] Sato and colleagues 31 have demonstrated that only one class of murine stem cell exists, although in 2 functional states distinguishable by CD34 expression. According to this model, CD34 Ϫ stem cells are quiescent and can be activated by different stimuli to generate a CD34 ϩ cell population with high engraftment potential. 32,33 In this study, we assessed the expression of P2Rs on highly purified CD34 ϩ HSCs and investigated the functional responses of Materials and methods ReagentsATP, UTP, cytidine triphosphate (CTP), guano...

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

“…For instance, ATP induces the proliferation of human HSC and contributed through P2X receptor activation during inflammation process [29,30]. UTP also induces proliferation and migration of HSCs [30,31] while adenosine potentiates the stimulatory effect of growth factors and cytokines on HSC proliferation and differentiation [8].…”

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…ATP and UTP have been shown to be potent stimulators of human hematopoietic stem cells both in vitro and in vivo (Lemoli et al, 2004). Thus, these extracellular nucleotides may provide a novel and powerful tool to modulate hematopoietic stem cell function to increase the number of transplantable cells in vivo in the event of bone marrow failure.…”

Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation

“…It has been proposed that extracellular ATP, via activation of purinergic P2 receptors (P2Rs), is an important regulator of inflammatory and immune response (12,13) by modulating B cells (14), monocytes (MO)/macrophages (15), eosinophils (16), and dendritic cells (DCs) (17,18). More recently, extracellular nucleotides have been shown capable to modulate mesenchymal as well as normal and leukemic hematopoietic stem cell functions (19)(20)(21)(22). However, currently, a coherent picture of ATP-mediated responses of T cells is not available, because of the contrasting results obtained in different studies (23)(24)(25)(26).…”