Micheli Laura, Caruso Maurizia, D'Andrea Giorgio, Volpe Daniel, Ceccarelli Manuela, Tirone Felice
Institute of Biochemistry and Cell Biology, National Research Council, Rome, Italy.
Onco-Hematology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Front Cell Dev Biol. 2025 May 30;13:1605116. doi: 10.3389/fcell.2025.1605116. eCollection 2025.
Adult mammalian brains generate new neurons throughout life in two main niches, the dentate gyrus of the hippocampus and the subventricular zone, starting from neural stem cells (NSCs). Adult hippocampal neurogenesis is crucial for learning and memory and decreases during aging. As defined in mouse models, NSCs, which are prevalently quiescent, develop into proliferating progenitor cells, neuroblasts, and immature and mature neurons. Two visions for NSC self-renewal in the dentate gyrus have been proposed, one postulating persistent self-renewal, with cycles of rest and reactivation even in old age, and the other proposing a short-lived NSC model. Single-cell RNA sequencing and clonal studies, discussed in this review, have shed light on the developmental steps of neurogenic cells and the modality of self-renewal, revealing the presence in the adult dentate gyrus of NSC heterogeneous populations, one long-lived and another rapidly depleted at an early age. Another relevant question is whether adult neurogenesis occurs in humans. A few single-cell RNA-seq studies show that new neurons, with prolonged neuronal maturation, are continuously generated at low frequency from stem/progenitor cells, which results in the accumulation of immature granule cell neurons. This suggests an important role of these cells in human neurogenesis and hence interspecies differences in the neurogenic process dynamics. This review is focused on transcriptomic studies that have faced these and other NSC issues by analyzing developmental trajectories of neural cells and NSCs gene expression profiles in specific experimental settings of hippocampal neurogenesis, and also in mouse models with deletion or overexpression of specific genes to reproduce neural pathologies.
成年哺乳动物的大脑在其一生中会在两个主要微环境中产生新的神经元，即海马体的齿状回和脑室下区，起始于神经干细胞（NSCs）。成年海马体神经发生对于学习和记忆至关重要，且在衰老过程中会减少。如在小鼠模型中所定义的，普遍处于静止状态的神经干细胞会发育为增殖性祖细胞、神经母细胞以及未成熟和成熟的神经元。关于齿状回中神经干细胞自我更新，已提出了两种观点，一种假设持续自我更新，即使在老年也存在休息和重新激活的循环，另一种则提出短期神经干细胞模型。本综述中讨论的单细胞RNA测序和克隆研究，已阐明了神经源性细胞的发育步骤以及自我更新的方式，揭示了成年齿状回中存在神经干细胞异质群体，一种寿命长，另一种在早期迅速耗尽。另一个相关问题是成年神经发生是否在人类中发生。一些单细胞RNA测序研究表明，具有延长神经元成熟过程的新神经元以低频率持续从干细胞/祖细胞产生，这导致未成熟颗粒细胞神经元的积累。这表明这些细胞在人类神经发生中具有重要作用，因此在神经发生过程动态方面存在种间差异。本综述聚焦于转录组学研究，这些研究通过分析神经细胞的发育轨迹以及在海马体神经发生的特定实验环境中神经干细胞的基因表达谱，还通过在具有特定基因缺失或过表达以重现神经病理的小鼠模型中，来面对这些以及其他神经干细胞问题。
