Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations

• Published in: Protein & cell Vol. 9; no. 4; pp. 351 - 364
• Main Authors: Shi, Zhanping, Geng, Yanan, Liu, Jiping, Zhang, Huina, Zhou, Liqiang, Lin, Quan, Yu, Juehua, Zhang, Kunshan, Liu, Jie, Gao, Xinpei, Zhang, Chunxue, Yao, Yinan, Zhang, Chong, Sun, Yi E.
• Format: Journal Article
• Language: English
• Published: Beijing Higher Education Press 01.04.2018; Springer Nature B.V; Oxford University Press
• Subjects: Aging; Aging - genetics; Animals; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; Biochemistry; Biomedical and Life Sciences; Brain - cytology; Brain - metabolism; Cell Biology; Cell cycle; Cell Differentiation - genetics; Cell Division - genetics; Cell growth; Cell proliferation; Cell Proliferation - genetics; Cognitive ability; Cytokines; Data processing; Developmental Biology; Erk1/2; Forebrain; Gene expression; Gene Expression Regulation - genetics; Human Genetics; Inflammation; Life Sciences; MAP kinase; Mice; Molecular modelling; Neural stem cells; Neural Stem Cells - metabolism; NSC/NPCs; Progenitor cells; Protein Science; Research Article; SEZ/SVZ; single cell transcriptome; Single-Cell Analysis; Stem Cells; Stem Cells - cytology; Stem Cells - metabolism; Transcription; Transcriptome - genetics; single cell transcriptome; Erk1/2; NSC/NPCs; aging; cell cycle; SEZ/SVZ
• ISSN: 1674-800X; 1674-8018
• DOI: 10.1007/s13238-017-0450-2

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.