Mitotic and Neurogenic Effects of Dehydroepiandrosterone (DHEA) on Human Neural Stem Cell Cultures Derived from the Fetal Cortex

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (9), p.3202-3207
• Main Authors: Suzuki, Masatoshi, Wright, Lynda S., Marwah, Padma, Lardy, Henry A., Svendsen, Clive N.
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological Sciences; Brain; Bromodeoxyuridine; Cell culture; Cell Differentiation; Cell Division; Cell growth; Cell lines; Cells, Cultured; Cellular differentiation; Cellular immunity; Cerebral Cortex - embryology; Cultured cells; Dehydroepiandrosterone - analogs & derivatives; Dehydroepiandrosterone - pharmacology; DNA Primers; DNA, Complementary; Effects; Humans; Mitosis - drug effects; Mitotic Index; N methyl D aspartate receptors; Neural stem cells; Neurology; Neurons; Neurons - cytology; Neurons - drug effects; Neuropeptides - genetics; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stem cells; Stem Cells - cytology; Stem Cells - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0307325101

Dehydroepiandrosterone (DHEA) is a neurosteroid with potential effects on neurogenesis and neuronal survival in humans. However, most studies on DHEA have been performed in rodents, and there is little direct evidence for biological effects on the human nervous system. Furthermore, the mechanism of its action is unknown. Here, we show that DHEA significantly increased the growth rates of human neural stem cells derived from the fetal cortex and grown with both epidermal growth factor (EGF) and leukemia inhibitory factor (LIF). However, it had no effect on cultures grown in either factor alone, suggesting a specific action on the EGF/LIF-responsive cell. Precursors of DHEA such as pregnenolone or six of its major metabolites, had no significant effect on proliferation rates. DHEA did not alter the small number (95%) of nestin-positive precursors. However, the number of glial fibrillary acidic protein-positive cells, its mRNA, and protein were significantly increased by DHEA. We found both N-methyl-D-aspartate and sigma 1 antagonists, but not GABA antagonists, could completely eliminate the effects of DHEA on stem cell proliferation. Finally we asked whether the EGF/LIF/DHEA-responsive stem cells had an increased potential for neurogenesis and found a 29% increase in neuronal production when compared to cultures grown in EGF/LIF alone. Together these data suggest that DHEA is involved in the maintenance and division of human neural stem cells. Given the wide availability of this neurosteroid, this finding has important implications for future use.