Bonaguidi Michael A, Peng Chian-Yu, McGuire Tammy, Falciglia Gustave, Gobeske Kevin T, Czeisler Catherine, Kessler John A
Davee Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois 60611, USA.
J Neurosci. 2008 Sep 10;28(37):9194-204. doi: 10.1523/JNEUROSCI.3314-07.2008.
New neurons are added to the adult hippocampus throughout life and contribute to cognitive functions, including learning and memory. It remains unclear whether ongoing neurogenesis arises from self-renewing neural stem cells (NSCs) or from multipotential progenitor cells that cannot self-renew in the hippocampus. This is primarily based on observations that neural precursors derived from the subventricular zone (SVZ) can be passaged long term, whereas hippocampal subgranular zone (SGZ) precursors are rapidly depleted by passaging. We demonstrate here that high levels of bone morphogenetic protein (BMP) signaling occur in hippocampal but not SVZ precursors in vitro, and blocking BMP signaling with Noggin is sufficient to foster hippocampal cell self-renewal, proliferation, and multipotentiality using single-cell clonal analysis. Moreover, NSC maintenance requires continual Noggin exposure, which implicates BMPs as crucial regulators of NSC aging. In vivo, Noggin is expressed in the adult dentate gyrus and limits BMP signaling in proliferative cells of the SGZ. Transgenic Noggin overexpression in the SGZ increases multiple precursor cell populations but proportionally increases the glial fibrillary acidic protein-positive cell population at the expense of other precursors, suggesting that Noggin acts on NSCs in vivo. To confirm this, we used a dual thymidine analog paradigm to repeatedly label slowly dividing cells over a long duration. We find that small populations of label-retaining cells exist in the SGZ and that Noggin overexpression increases their numbers. Thus, we propose that the adult hippocampus contains a population of NSCs, which can be expanded both in vitro and in vivo by blocking BMP signaling.
成年海马体在一生中都会不断生成新的神经元,并对包括学习和记忆在内的认知功能产生影响。目前尚不清楚持续的神经发生是源于自我更新的神经干细胞(NSC),还是源于海马体中无法自我更新的多能祖细胞。这主要基于以下观察结果:源自脑室下区(SVZ)的神经前体细胞可以长期传代,而海马体颗粒下区(SGZ)的前体细胞在传代后会迅速耗尽。我们在此证明,体外实验中,海马体前体细胞而非SVZ前体细胞中存在高水平的骨形态发生蛋白(BMP)信号,并且使用单细胞克隆分析发现,用Noggin阻断BMP信号足以促进海马体细胞的自我更新、增殖和多能性。此外,NSC的维持需要持续暴露于Noggin,这表明BMP是NSC衰老的关键调节因子。在体内,Noggin在成年齿状回中表达,并限制SGZ增殖细胞中的BMP信号。SGZ中Noggin的转基因过表达增加了多种前体细胞群,但以牺牲其他前体细胞为代价,成比例地增加了胶质纤维酸性蛋白阳性细胞群,这表明Noggin在体内作用于NSC。为了证实这一点,我们使用了双胸苷类似物范式,在长时间内反复标记缓慢分裂的细胞。我们发现在SGZ中存在少量标记保留细胞,并且Noggin过表达增加了它们的数量。因此,我们提出成年海马体中存在一群NSC,通过阻断BMP信号,它们在体外和体内均可扩增。