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Blood, 15 January 2007, Vol. 109, No. 2, pp. 533-542.
Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2006-01-035634.
 Previous Article | Next Article 
Submitted January 9, 2006
Accepted September 2, 2006
The extracellular nucleotide UTP is a potent inducer of
hematopoietic stem cell migration
Lara Rossi, Rossella Manfredini, Francesco Bertolini, Davide Ferrari, Miriam Fogli, Roberta Zini, Simona Salati, Valentina Salvestrini, Sara Gulinelli, Elena Adinolfi, Sergio Ferrari, Francesco Di Virgilio, Michele Baccarani, and Roberto M Lemoli*
Institute of Hematology and Medical Oncology, University of Bologna, Bologna, Italy
Dept of Biomedical Sciences, Section of Biochemistry, Univ. of Modena & Reggio Emilia, Modena, Italy
Division of Hematology-Oncology, Dept. of Medicine, European Institute of Oncology, Milan, Italy
Dept. of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy
* Corresponding author; email: rmlemoli{at}med.unibo.it.
Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and non-peptide molecules. Extracellular nucleotides and their cognate P2 receptors are emerging as key-factors of inflammation and related chemotactic responses. In this study, we investigated the activity of extracellular adenosine-triphosphate (ATP) and uridine-triphosphate (UTP) on CXCL12-stimulated CD34+ HSC chemotaxis. In vitro, UTP significantly improved HSC migration, inhibited cell membrane CXCR4 down-regulation by migrating CD34+ cells and increased cell adhesion to fibronectin. In vivo, pre-incubation with UTP significantly enhanced the BM homing efficiency of human CD34+ cells in immunodeficient mice. Pertussis toxin blocked CXCL12- and UTP-dependent chemotactic responses, suggesting that G-protein alpha-subunits (G i) may provide a converging signal for CXCR4- and P2Y-activated transduction pathways. In addition, gene expression profiling of UTP-and CXCL12-treated CD34+ cells and in vitro inhibition assays demonstrated that Rho guanosine 5' - triphosphatases (GTPase) Rac2 and downstream effectors Rho GTPase- activated kinases 1 and 2 (ROCK1/2) are involved in UTP-promoted/CXCL12-dependent HSC migration. Our data suggest that UTP may physiologically modulate the homing of HSCs to the BM, in concert with CXCL12, via the activation of converging signaling pathways between CXCR4 and P2Y receptors, involving G i proteins and RhoGTPases.
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