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衰老神经祖细胞的单细胞RNA测序揭示了兴奋性神经元潜能的丧失以及一个具有转录免疫反应的细胞群体。

Single-cell RNA sequencing of aging neural progenitors reveals loss of excitatory neuron potential and a population with transcriptional immune response.

作者信息

Fritze Jonas, Lang Stefan, Sommarin Mikael, Soneji Shamit, Ahlenius Henrik

机构信息

Stem Cells, Aging and Neurodegeneration Group, Faculty of Medicine, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Lund Stem Cell Center, Lund, Sweden.

出版信息

Front Neurosci. 2024 Aug 9;18:1400963. doi: 10.3389/fnins.2024.1400963. eCollection 2024.

Abstract

In the adult murine brain, neural stem cells (NSCs) can be found in two main niches: the dentate gyrus (DG) and the subventricular zone (SVZ). In the DG, NSCs produce intermediate progenitors (IPs) that differentiate into excitatory neurons, while progenitors in the SVZ migrate to the olfactory bulb (OB), where they mainly differentiate into inhibitory interneurons. Neurogenesis, the process of generating new neurons, persists throughout life but decreases dramatically with aging, concomitantly with increased inflammation. Although many cell types, including microglia, undergo significant transcriptional changes, few such changes have been detected in neural progenitors. Furthermore, transcriptional profiles in progenitors from different neurogenic regions have not been compared on a single-cell level, and little is known about how they are affected by aging-related inflammation. We have generated a single cell RNA sequencing dataset enriched for IPs, which revealed that most aged neural progenitors only acquire minor transcriptional changes. However, progenitors set to become excitatory neurons decrease faster than others. In addition, a population in the aged SVZ, not detected in the OB, acquired major transcriptional activation related to immune responses. This suggests that differences in age related neurogenic decline between regions is not due to tissue differences but rather cell type specific intrinsic transcriptional programs, and that subset of neuroblasts in the SVZ react strongly to age related inflammatory cues.

摘要

在成年小鼠大脑中,神经干细胞(NSCs)主要存在于两个特定区域:齿状回(DG)和脑室下区(SVZ)。在齿状回中,神经干细胞产生中间祖细胞(IPs),后者分化为兴奋性神经元,而脑室下区的祖细胞则迁移至嗅球(OB),并在那里主要分化为抑制性中间神经元。神经发生,即产生新神经元的过程,在整个生命过程中持续存在,但随着衰老而显著减少,同时炎症增加。尽管包括小胶质细胞在内的许多细胞类型会发生显著的转录变化,但在神经祖细胞中很少检测到此类变化。此外,尚未在单细胞水平上比较来自不同神经发生区域的祖细胞的转录谱,对于它们如何受到与衰老相关的炎症影响也知之甚少。我们生成了一个富含中间祖细胞的单细胞RNA测序数据集,该数据集显示,大多数衰老的神经祖细胞仅发生轻微的转录变化。然而,注定要成为兴奋性神经元的祖细胞比其他祖细胞减少得更快。此外,在衰老的脑室下区中存在一群在嗅球中未检测到的细胞,它们获得了与免疫反应相关的主要转录激活。这表明,不同区域与年龄相关的神经发生衰退差异并非由于组织差异,而是由于细胞类型特异性的内在转录程序,并且脑室下区的一部分神经母细胞对与年龄相关的炎症信号有强烈反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77bd/11341460/608a463edcfc/fnins-18-1400963-g0001.jpg

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