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J. Biol. Chem., Vol. 280, Issue 7, 5343-5349, February 18, 2005

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Concentrative Uptake of Cyclic ADP-ribose Generated by BST-1⁺ Stroma Stimulates Proliferation of Human Hematopoietic Progenitors^*

Marina Podestà, Federica Benvenuto, Anna Pitto¶, Osvaldo Figari, Andrea Bacigalupo, Santina Bruzzone||, Lucrezia Guida||, Luisa Franco**, Laura Paleari||, Nicoletta Bodrato||, Cesare Usai, Antonio De Flora||, and Elena Zocchi||¶¶

From the Department of Hematology, 2nd Division, Pad.5, S. Martino Hospital, Largo R. Benzi 10, 16132 Genova, Italy, the Biotechnology Research Laboratories, Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, 27100 Pavia, Italy, the ^||Department of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy, the ^**G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genova, Italy, and the Institute of Biophysics, CNR, Via De Marini 6, 16149 Genova, Italy

Cyclic ADP-ribose (cADPR) is an intracellular calcium mobilizer generated from NAD⁺ by the ADP-ribosyl cyclases CD38 and BST-1. cADPR, both exogenously added and paracrinally produced by a CD38⁺ feeder layer, has recently been demonstrated to stimulate the in vitro proliferation of human hemopoietic progenitors (HP) and also the in vivo expansion of hemopoietic stem cells. The low density of BST-1 expression on bone marrow (BM) stromal cells and the low specific activity of the enzyme made it unclear whether cADPR generation by a BST-1⁺ stroma could stimulate HP proliferation in the BM microenvironment. We developed and characterized two BST-1⁺ stromal cell lines, expressing an ectocellular cyclase activity similar to that of BST-1⁺ human mesenchymal stem cells, the precursors of BM stromal cells. Long term co-culture of cord blood-derived HP over these BST-1⁺ feeders determined their expansion. Influx of paracrinally generated cADPR into clonogenic HP was mediated by a concentrative, nitrobenzylthioinosine- and dipyridamole-inhibitable nucleoside transporter, this providing a possible explanation to the effectiveness of the hormone-like concentrations of the cyclic nucleotide measured in the medium conditioned by BST-1⁺ feeders. These results suggest that the BST-1-catalyzed generation of extracellular cADPR, followed by the concentrative uptake of the cyclic nucleotide by HP, may be physiologically relevant in normal hemopoiesis.

Received for publication, July 16, 2004 , and in revised form, November 26, 2004.

^* This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), from the Italian Ministry of Education, University and Scientific Research (MURST-PRIN 2002, MIUR FIRB RBAUO19A3C, MIUR FIRB RBNE01ERXR), the University of Genova, CNR (Target Project on Biotechnology), Consorzio Interuniversitario per le Biotecnologie (CIB), and Fondazione Cassa di Risparmio di Genova e Imperia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

Recipient of a Ph.D. fellowship (School of Doctorate of Biotechnology of the University of Genova) supported by Dompé S.p.A.

^¶¶ To whom correspondence should be addressed: Dept. of Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy. Tel.: 39-10-3538151; Fax: 39-10-354415; E-mail: ezocchi{at}unige.it.

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