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.

成体神经干细胞（Neural Stem Cells，NSCs）的异质性群体参与脑稳态维持与损伤后再生修复。成体神经干细胞激活与静息的平衡，以及谱系特异性转录因子的诱导，或可促成神经元与胶质细胞的命运多样性。为鉴定调控上述特性的分子特征，我们对未偏倚的成体室管膜下区NSCs群体开展了单细胞测序。本分析鉴定出一个离散的休眠NSC亚群，该亚群在机体稳态条件下即已表达不同组合的谱系特异性转录因子。休眠NSCs在激活前会进入预激活静息状态，此过程伴随糖酵解代谢、Notch信号通路及骨形态发生蛋白（Bone Morphogenetic Protein，BMP）信号通路的下调，同时谱系特异性转录因子与蛋白质合成水平出现上调。在脑缺血应激条件下，干扰素γ信号通路可诱导休眠NSC亚群进入预激活静息状态。本研究揭示了调控NSC激活与谱系预启动的通用原则，为脑内再生医学开辟了潜在应用途径。