J
James Michael H
Guest
Proc Natl Acad Sci U S A. 2004 Feb 18 [Epub ahead of print] Links Mitotic and neurogenic effects of
dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex.
Suzuki M, Wright LS, Marwah P, Lardy HA, Svendsen CN.
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 (<3%) of newly formed neuroblasts or the large 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.
dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex.
Suzuki M, Wright LS, Marwah P, Lardy HA, Svendsen CN.
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 (<3%) of newly formed neuroblasts or the large 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.