Extracelluar cyclic ADP-ribose increases intracellular free calcium concentration and stimulates proliferation of human hemopoietic progenitors

Marina Podestà, Elena Zocchi, Anna Pitto, Cesare Usai, Luisa Franco, Santina Bruzzone, Lucrezia Guida, Andrea Bacigalupo, David T. Scadden, Timothy F. Walseth, Antonio De Flora, Antonio Daga

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)680-690
Number of pages11
JournalFASEB Journal
Volume14
Issue number5
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Bone marrow cells
  • Cytokine-like activity of cyclic ADP-ribose
  • Expansion of hemopoietic progenitors
  • Intracellular calcium homeostasis

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