Suzuki Masatoshi, Wright Lynda S, Marwah Padma, Lardy Henry A, Svendsen Clive N
Department of Anatomy and the Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705-2280, USA.
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3202-7. doi: 10.1073/pnas.0307325101. Epub 2004 Feb 18.
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.
脱氢表雄酮（DHEA）是一种神经甾体，对人类神经发生和神经元存活具有潜在影响。然而，大多数关于DHEA的研究是在啮齿动物中进行的，几乎没有直接证据表明其对人类神经系统有生物学作用。此外，其作用机制尚不清楚。在这里，我们表明，DHEA显著提高了源自胎儿皮质并在表皮生长因子（EGF）和白血病抑制因子（LIF）共同作用下培养的人类神经干细胞的生长速率。然而，它对仅在其中一种因子作用下培养的细胞没有影响，这表明它对EGF/LIF反应性细胞有特定作用。DHEA的前体如孕烯醇酮或其六种主要代谢产物对增殖速率没有显著影响。DHEA没有改变少量（<3%）新形成的神经母细胞或大量（>95%）巢蛋白阳性前体细胞的数量。然而，DHEA显著增加了胶质纤维酸性蛋白阳性细胞的数量及其mRNA和蛋白质水平。我们发现N-甲基-D-天冬氨酸和西格玛1拮抗剂而非GABA拮抗剂能够完全消除DHEA对干细胞增殖的影响。最后，我们研究了EGF/LIF/DHEA反应性干细胞是否具有增加的神经发生潜能，结果发现与仅在EGF/LIF中培养的细胞相比，神经元生成增加了29%。这些数据共同表明，DHEA参与了人类神经干细胞的维持和分裂。鉴于这种神经甾体广泛存在，这一发现对其未来应用具有重要意义。
