Extracellular purine nucleosides stimulate cell division and morphogenesis: pathological and physiological implications.

Extracellular purine nucleosides and nucleotides are ubiquitous, phylogenetically ancient, intercellular signals. Purines are released from hypoxic, damaged or dying cells. Purine nucleosides and nucleotides are potent mitogens for several types of cells such as fibroblasts, endothelial cells and neuroglia. They also induce other cell types to differentiate. For example, they act synergistically with nerve growth factor to stimulate neurite outgrowth from a pheochromocytoma cell line (PC12). We propose that after injury to tissues, including the central nervous system, purine nucleosides and nucleotides interact synergistically with other growth factors. They stimulate proliferation and morphological changes in the various cell types involved in the wound healing response. In the central nervous system this response includes glial proliferation, capillary endothelial cell proliferation, and sprouting of nerve axons. Since many actions of extracellular purines are mediated through specific cell surface receptors, this hypothesis has broad pharmacological implications.

Stimulation of astrocyte proliferation by purine and pyrimidine nucleotides and nucleosides.

Proliferation of brain astrocytes as a result of cell death has been well documented in vivo. Dying cells release purine and pyrimidine nucleosides and nucleotides and their deoxy derivatives both from soluble intracellular pools and from DNA and RNA. Previously, we have observed that purine nucleosides and nucleotides stimulate chick astrocyte proliferation in vitro. To further our analysis, we questioned whether pyrimidines or the deoxy derivatives of purine nucleosides and nucleotides might also be astrocyte mitogens. Pyrimidine nucleosides, nucleotides, and their deoxynucleotide derivatives were uniformly inactive. In contrast, deoxyguanosine, deoxyadenosine, and their mono-, di-, and triphosphates stimulated thymidine incorporation into astrocytes at concentrations similar to those at which their ribonucleoside and ribonucleotide analogues were active. Inosine, IMP, ITP, and hypoxanthine were active, whereas xanthine and xanthosine were not. However, XMP, XDP, and XTP stimulated thymidine incorporation. The effects of the nucleosides and deoxynucleosides were inhibited by antagonists of adenosine A2 receptors. These data indicate that most purine nucleosides, deoxynucleosides, and their 5' mono, di-, and triphosphate derivatives released from damaged cells are capable of stimulating astrocyte proliferation in vitro and may contribute to astrocyte proliferation in vivo following injury to the CNS.