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* Department of Hematology, S. Martino Hospital, Genova, Italy;
Department of Experimental Medicine, Section of Biochemistry, University of Genova, Italy;
Institute of Cybernetics and Biophysics, National Research Council, Genova, Italy;
§ Department of Experimental Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
** Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA; and
IST, National Institute for Cancer Research, Genova, Italy
3Correspondence: Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy. E-mail: toninodf{at}unige.it
Cyclic ADP-ribose (cADPR) is a universal second messenger that regulates many calcium-related cellular events by releasing calcium from intracellular stores. Since these events include enhanced cell proliferation and since the bone marrow harbors both ectoenzymes that generate cADPR from NAD+ (CD38 and BST-1), we investigated the effects of extracellular cADPR on human hemopoietic progenitors (HP). Exposure of HP to 100 µM cADPR for 24 h induced a significant increase in colony output (P<0.01) and colony size (P<0.003). A horizontal expansion of HP, as demonstrated by a markedly increased replating efficiency in semisolid medium (up to 700 times compared to controls), was also observed, indicating that cADPR priming can affect cell growth for multiple generations over several weeks after exposure. Influx of extracellular cADPR into the cells was demonstrated, and a causal relationship between the functional effects and the increase of intracellular free calcium concentration induced by cADPR on HP was established through the use of specific antagonists. Similar effects on HP were produced by nanomolar concentrations of the nonhydrolyzable cADPR analog 3-deaza-cADPR. These data demonstrate that extracellular cADPR behaves as a cytokine enhancing the proliferation of human HP, a finding that may have biomedical applications for the ex vivo expansion of hemopoietic cells.—Podestà, M., Zocchi, E., Pitto, A., Usai, C., Franco, L., Bruzzone, S., Guida, L., Bacigalupo, A., Scadden, D. T., Walseth, T. F., De Flora, A., Daga, A. Extracellular cyclic ADP-ribose increases intracellular free calcium concentration and stimulates proliferation of human hemopoietic progenitors.
Key Words: bone marrow cells • intracellular calcium homeostasis • cytokine-like activity of cyclic ADP-ribose • expansion of hemopoietic progenitors
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