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, Elena Zocchi

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Abstract

Cyclic ADP-ribose (cADPR) is an intracellular calcium mobilizes 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.

Original languageEnglish
Pages (from-to)5343-5349
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number7
DOIs
Publication statusPublished - Feb 18 2005

ASJC Scopus subject areas

  • Biochemistry

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    Podestà, M., Benvenuto, F., Pitto, A., Figari, O., Bacigalupo, A., Bruzzone, S., Guida, L., Franco, L., Paleari, L., Bodrato, N., Usai, C., De Flora, A., & Zocchi, E. (2005). Concentrative uptake of cyclic ADP-ribose generated by BST-1+ stroma stimulates proliferation of human hematopoietic progenitors. Journal of Biological Chemistry, 280(7), 5343-5349. https://doi.org/10.1074/jbc.M408085200