Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
Department of Psychiatry and Biobehavioral Sciences and Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Protein Cell. 2018 Apr;9(4):351-364. doi: 10.1007/s13238-017-0450-2. Epub 2017 Jul 26.
Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSC/NPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSC/NPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSC/NPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Interestingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The Erk/Mapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSC/NPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSC/NPCs and their microenvironment in the context of the aging brain.
衰老相关的认知能力下降与神经干细胞/祖细胞（NSC/NPCs）活性减弱有关，表现为增殖减少、产生神经元的能力降低以及向星形胶质细胞分化增加。虽然基因转录变化客观地揭示了细胞经历各种生物学过程的分子改变，但由于大脑细胞组成的巨大异质性和 NSC/NPC 所在的复杂细胞微环境，寻找 NSC/NPC 衰老的分子机制一直面临挑战。此外，脑 NSC/NPC 本身并不是一个同质群体，这使得揭示 NSC/NPC 亚型特异性衰老机制更加困难。在这里，我们使用年轻和衰老小鼠前脑室管膜和室下区的基于群体和单细胞转录组分析以及全面的“大数据”处理，报告 NSC/NPC 存在于衰老大脑中相当炎症的环境中，这可能导致其向星形胶质细胞而非神经元分化的偏向。此外，单细胞转录组分析显示，不同衰老的 NSC/NPC 亚群虽然增殖能力都降低，但使用不同的基因转录程序来调节与年龄相关的细胞周期下降。有趣的是，细胞增殖能力的变化不受炎症细胞因子的影响，而可能是由细胞内在机制引起的。Erk/Mapk 通路似乎在调节 NSC/NPC 克隆扩增能力的年龄依赖性变化中起着至关重要的作用。总之，这项研究是首例使用基于群体和单细胞的转录组分析来揭示衰老大脑中不同 NSC/NPC 及其微环境之间分子相互作用的研究。
