Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury

Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Single cell RNAseq of cells isolated from their in vivo niche in the subventricular zone, Striatum and Cortex during homeostasis as well as following ischemic injury. In total 272 single cells. (<WT>: homeostasis samples; <Ischemic_injured> and <Ischemic_injured_and_Interferon_gamma_knockout>: samples following ischemic injuried).异质性成体神经干细胞（neural stem cells, NSCs）池参与大脑稳态维持与损伤后的脑再生。神经干细胞的激活与静息平衡，以及谱系特异性转录因子的诱导，或为神经元与胶质细胞命运多样性的重要成因。为阐明调控上述特性的分子特征，我们对无偏倚富集的成体脑室下区神经干细胞开展了单细胞测序。本次分析鉴定出一个离散的静息神经干细胞亚群，该亚群在稳态条件下即已表达多种不同组合的谱系特异性转录因子。静息神经干细胞在激活前会进入致敏静息状态，此过程伴随糖酵解代谢、Notch信号与BMP信号的下调，同时谱系特异性转录因子与蛋白质合成水平上调。在脑缺血刺激下，干扰素γ信号通路可诱导静息神经干细胞亚群进入致敏静息状态。本研究揭示了神经干细胞激活与谱系致敏的核心调控原则，为脑再生医学开辟了潜在研究方向。 本数据集包含稳态及缺血性损伤条件下，从脑室下区、纹状体与皮层的体内微环境中分离得到的细胞的单细胞RNA测序（RNAseq）数据，共计272个单细胞。其中<野生型（wild type, WT）>为稳态对照组样本；<缺血损伤组>与<缺血损伤+干扰素γ敲除组>为缺血损伤后样本。