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

doi:10.1007/s13238-017-0450-2

Protein Cell

2018, Vol. 9

Issue (4) : 351-364 https://doi.org/10.1007/s13238-017-0450-2

RESEARCH ARTICLE

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

Zhanping Shi¹, Yanan Geng¹, Jiping Liu¹, Huina Zhang¹, Liqiang Zhou¹, Quan Lin^1,², Juehua Yu¹, Kunshan Zhang¹, Jie Liu¹, Xinpei Gao¹, Chunxue Zhang¹, Yinan Yao¹, Chong Zhang¹, Yi E. Sun^1,^2,³(

)

¹. Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
². 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
³. Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China

Download: PDF(3009 KB)
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

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.

Keywords NSC/NPCs SEZ/SVZ single cell transcriptome aging cell cycle Erk1/2

Corresponding Author(s): Yi E. Sun

Issue Date: 27 April 2018

Cite this article:

Zhanping Shi,Yanan Geng,Jiping Liu, et al. Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations[J]. Protein Cell, 2018, 9(4): 351-364.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-017-0450-2
https://academic.hep.com.cn/pac/EN/Y2018/V9/I4/351

1	Beckervordersandforth Ret al. (2010) In vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell 7:744–758 https://doi.org/10.1016/j.stem.2010.11.017
2	Bonni Aet al. (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483 https://doi.org/10.1126/science.278.5337.477
3	Coskun Vet al. (2008) CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. PNAS 105(3):1026–1031 https://doi.org/10.1073/pnas.0710000105
4	Doetsch Fet al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716 https://doi.org/10.1016/S0092-8674(00)80783-7
5	Duan Het al. (2015) Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury. PNAS 112(43):13360–13365 https://doi.org/10.1073/pnas.1510176112
6	Dulken BWet al. (2017) Single-cell transcriptomic analysis defines heterogeneity and transcriptional dynamics in the adult neural stem cell lineage. Cell Rep 18:777–790 https://doi.org/10.1016/j.celrep.2016.12.060
7	Enwere Eet al. (2004) Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24:8354–8365 https://doi.org/10.1523/JNEUROSCI.2751-04.2004
8	Kim Det al. (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12:357–360 https://doi.org/10.1038/nmeth.3317
9	Kim DHet al. (2015) Single-cell transcriptome analysis reveals dynamic changes in lncRNA expression during reprogramming. Cell Stem Cell 16:88–101 https://doi.org/10.1016/j.stem.2014.11.005
10	Laurens VDM, Hinton G (2008) Visualizing data using t-SNE. J Mach Learn Res 9(2605):2579–2605
11	Llorens-Bobadilla Eet al. (2015) Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17:329–340 https://doi.org/10.1016/j.stem.2015.07.002
12	Love MIet al. (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550 https://doi.org/10.1186/s13059-014-0550-8
13	Luo Yet al. (2015) Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell 161:1175–1186 https://doi.org/10.1016/j.cell.2015.04.001
14	Maslov AYet al. (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733 https://doi.org/10.1523/JNEUROSCI.4608-03.2004
15	Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702 https://doi.org/10.1016/j.neuron.2011.05.001
16	Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132:598–611 https://doi.org/10.1016/j.cell.2008.01.038
17	Nolan DJet al. (2013) Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell 26:204–219 https://doi.org/10.1016/j.devcel.2013.06.017
18	Pertea Met al. (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 3:290–295 https://doi.org/10.1038/nbt.3122
19	Picelli Set al. (2013) Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat Methods 10:1096–1098 https://doi.org/10.1038/nmeth.2639
20	Picelli Set al. (2014) Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc 9:171–181 https://doi.org/10.1038/nprot.2014.006
21	Satoh Yet al.(2011) Deletion of ERK1 and ERK2 in the CNS causes cortical abnormalities and neonatal lethality: Erk1 deficiency enhances the impairment of neurogenesis in Erk2-deficient mice. J Neurosci 31:1149–1155 https://doi.org/10.1523/JNEUROSCI.2243-10.2011
22	Shalek AKet al. (2013) Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498:236–240 https://doi.org/10.1038/nature12172
23	Shapiro E, Biezuner T, Linnarsson S (2013) Single-cell sequencingbased technologies will revolutionize whole-organism science. Nat Rev Genet 14:618–630 https://doi.org/10.1038/nrg3542
24	Sun Yet al. (2001)Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376 https://doi.org/10.1016/S0092-8674(01)00224-0
25	Vithayathil Jet al. (2015) Dentate gyrus development requires ERK activity to maintain progenitor population and MAPK pathway feedback regulation. J Neurosci 35:6836–6848 https://doi.org/10.1523/JNEUROSCI.4196-14.2015
26	Yanget al. (2015) NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. PNAS 112(43):13354–13359 https://doi.org/10.1073/pnas.1510194112
27	Zhang Ket al. (2014) Identification and functional analysis of long noncoding RNAs in mouse cleavage stage embryonic development based on single cell transcriptome data. BMC Genom 15:845 https://doi.org/10.1186/1471-2164-15-845
28	Zhao Cet al. (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660 https://doi.org/10.1016/j.cell.2008.01.033
29	Zhenget al. (2017) Massively parallel digital transcriptional profiling of single cells. Nat Commun 8:14049 https://doi.org/10.1038/ncomms14049

[1]	PAC-0351-17208-SY_suppl_1	Download
[2]	PAC-0351-17208-SY_suppl_2	Download
[3]	PAC-0351-17208-SY_suppl_3	Download

[1]	Shijia Bi, Zunpeng Liu, Zeming Wu, Zehua Wang, Xiaoqian Liu, Si Wang, Jie Ren, Yan Yao, Weiqi Zhang, Moshi Song, Guang-Hui Liu, Jing Qu. SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer[J]. Protein Cell, 2020, 11(7): 483-504.
[2]	Jianwei Liu, Mengdi Wang, Le Sun, Na Clara Pan, Changjiang Zhang, Junjing Zhang, Zhentao Zuo, Sheng He, Qian Wu, Xiaoqun Wang. *Integrative analysis of in vivo* recording with single-cell RNA-seq data reveals molecular properties of light-sensitive neurons in mouse V1**[J]. Protein Cell, 2020, 11(6): 417-432.
[3]	Yunxiang Yang, Pan Yang, Nan Wang, Zhonghao Chen, Dan Su, Z. Hong Zhou, Zihe Rao, Xiangxi Wang. Architecture of the herpesvirus genomepackaging complex and implications for DNA translocation[J]. Protein Cell, 2020, 11(5): 339-351.
[4]	Yingfeng Zheng, Xiuxing Liu, Wenqing Le, Lihui Xie, He Li, Wen Wen, Si Wang, Shuai Ma, Zhaohao Huang, Jinguo Ye, Wen Shi, Yanxia Ye, Zunpeng Liu, Moshi Song, Weiqi Zhang, Jing-Dong J. Han, Juan Carlos Izpisua Belmonte, Chuanle Xiao, Jing Qu, Hongyang Wang, Guang-Hui Liu, Wenru Su. A human circulating immune cell landscape in aging and COVID-19[J]. Protein Cell, 2020, 11(10): 740-770.
[5]	Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu. Chemical screen identifies a geroprotective role of quercetin in premature aging[J]. Protein Cell, 2019, 10(6): 417-435.
[6]	Nan Zhou, Kaili Liu, Yue Sun, Ying Cao, Jing Yang. Transcriptional mechanism of IRF8 and PU.1 governs microglial activation in neurodegenerative condition[J]. Protein Cell, 2019, 10(2): 87-103.
[7]	Ying Cao, Huanhuan Wang, Wenwen Zeng. Whole-tissue 3D imaging reveals intra-adipose sympathetic plasticity regulated by NGF-TrkA signal in cold-induced beiging[J]. Protein Cell, 2018, 9(6): 527-539.
[8]	Zeming Wu, Weiqi Zhang, Moshi Song, Wei Wang, Gang Wei, Wei Li, Jinghui Lei, Yu Huang, Yanmei Sang, Piu Chan, Chang Chen, Jing Jing, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Guang-Hui Liu. Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome[J]. Protein Cell, 2018, 9(4): 333-350.
[9]	Ying Li,Weizhou Zhang,Liang Chang,Yan Han,Liang Sun,Xiaojun Gong,Hong Tang,Zunpeng Liu,Huichao Deng,Yanxia Ye,Yu Wang,Jian Li,Jie Qiao,Jing Qu,Weiqi Zhang,Guang-Hui Liu. Vitamin C alleviates aging defects in a stem cell model for Werner syndrome[J]. Protein Cell, 2016, 7(7): 478-488.
[10]	Ruijuan Sun,Heqi Cao,Xudong Zhu,Jun-Ping Liu,Erdan Dong. Current aging research in China[J]. Protein Cell, 2015, 6(5): 314-321.
[11]	Shrestha Ghosh,Zhongjun Zhou. SIRTain regulators of premature senescence and accelerated aging[J]. Protein Cell, 2015, 6(5): 322-333.
[12]	Caiguo Zhang,Fan Zhang. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities[J]. Protein Cell, 2015, 6(2): 88-100.
[13]	Dengwen Li,Xiaodong Sun,Linlin Zhang,Bing Yan,Songbo Xie,Ruming Liu,Min Liu,Jun Zhou. Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells[J]. Protein Cell, 2014, 5(3): 214-223.
[14]	Caiguo Zhang. Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control[J]. Protein Cell, 2014, 5(10): 750-760.
[15]	Fang Hu,Feng Liu. Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations[J]. Protein Cell, 2014, 5(1): 21-35.

Viewed

Full text

Abstract

Cited

Shared

Discussed