Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland.
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
Nat Neurosci. 2021 Feb;24(2):225-233. doi: 10.1038/s41593-020-00759-4. Epub 2020 Dec 21.
Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.
神经干细胞（NSCs）在哺乳动物海马体中终生产生神经元。然而，成年大脑中单个 NSCs 长期自我更新的潜力尚不清楚。我们使用双光子显微镜，通过由干细胞表达基因 GLI 家族锌指 1（Gli1）或achaete-scute 同源物 1（Ascl1）的调节元件驱动的条件重组，对 NSCs 进行基因标记，并对其进行追踪。通过对 NSCs 及其祖细胞的活体成像，我们确定了一个Gli1 靶向 NSCs 群体，该群体在成年海马体中表现出长期自我更新。相比之下，一旦被激活，Ascl1 靶向的 NSCs 在耗尽之前经历有限的增殖活性。通过单细胞 RNA 测序，我们表明 Gli1 和 Ascl1 靶向的细胞具有高度相似但又不同的转录谱，支持存在具有不同行为特性的异质 NSC 群体。因此，我们在这里鉴定出具有长期自我更新能力的 NSCs，这些 NSCs 有助于成年海马体中新神经元的产生。
