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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.

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HEMATOPOIESIS

The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration

Lara Rossi1, Rossella Manfredini2, Francesco Bertolini3, Davide Ferrari4, Miriam Fogli1, Roberta Zini2, Simona Salati2, Valentina Salvestrini1, Sara Gulinelli4, Elena Adinolfi4, Sergio Ferrari2, Francesco Di Virgilio4, Michele Baccarani1, and Roberto M. Lemoli1,

1 Institute of Hematology and Medical Oncology "L. & A. Seràgagnoli," University of Bologna, and Stem Cell Research Center, S. Orsola-Malpighi Hospital, Bologna, Italy; 2 Department of Biomedical Sciences, Section of Biochemistry, University of Modena and Reggio Emilia, Modena, Italy; 3 Division of Hematology-Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy; 4 Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Italy

Homing and engraftment of hematopoietic stem cells (HSCs) to the bone marrow (BM) involve a complex interplay between chemokines, cytokines, and nonpeptide 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, preincubation 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{alpha}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'-triphosphatase (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{alpha}i proteins and RhoGTPases.


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