Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging.
Animals
Basic Helix-Loop-Helix Transcription Factors
/ biosynthesis
Cell Lineage
Female
Gene Expression Profiling
Hippocampus
/ cytology
Homeodomain Proteins
/ biosynthesis
Intravital Microscopy
Male
Metallothionein 3
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Fluorescence, Multiphoton
Nerve Regeneration
Nerve Tissue Proteins
/ biosynthesis
Neural Stem Cells
/ physiology
Single-Cell Analysis
Zinc Finger Protein GLI1
/ biosynthesis
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
19
11
2019
accepted:
13
11
2020
pubmed:
23
12
2020
medline:
20
3
2021
entrez:
22
12
2020
Statut:
ppublish
Résumé
Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.
Identifiants
pubmed: 33349709
doi: 10.1038/s41593-020-00759-4
pii: 10.1038/s41593-020-00759-4
pmc: PMC7116750
mid: EMS114906
doi:
Substances chimiques
Ascl1 protein, mouse
0
Basic Helix-Loop-Helix Transcription Factors
0
Gli1 protein, mouse
0
Hod protein, mouse
0
Homeodomain Proteins
0
Metallothionein 3
0
Nerve Tissue Proteins
0
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
225-233Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : European Research Council
ID : 670757
Pays : International
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106187
Pays : United Kingdom
Organisme : Swiss National Science Foundation
ID : 157859
Pays : Switzerland
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : BSCGI0_157859
Organisme : Wellcome Trust
ID : 098357
Pays : United Kingdom
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : Stembar
Organisme : Wellcome Trust
ID : FC001089
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001089
Pays : United Kingdom
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : Braincompath
Organisme : Cancer Research UK
ID : FC001089
Pays : United Kingdom
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 310030_196869
Organisme : Wellcome Trust
Pays : United Kingdom
Références
Gage, F. H. Adult neurogenesis in mammals. Science 364, 827–828 (2019).
Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018).
doi: 10.1038/nature25975
pubmed: 29513649
pmcid: 6179355
Goncalves, J. T., Schafer, S. T. & Gage, F. H. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167, 897–914 (2016).
doi: 10.1016/j.cell.2016.10.021
pubmed: 27814520
Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).
doi: 10.1038/3305
pubmed: 9809557
Knoth, R. et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5, e8809 (2010).
doi: 10.1371/journal.pone.0008809
pubmed: 20126454
pmcid: 2813284
Moreno-Jimenez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019).
doi: 10.1038/s41591-019-0375-9
pubmed: 30911133
Tobin, M. K. et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell 24, 974–982 (2019).
doi: 10.1016/j.stem.2019.05.003
pubmed: 31130513
pmcid: 6608595
Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013).
doi: 10.1016/j.cell.2013.05.002
pubmed: 23746839
pmcid: 4394608
Shin, J. et al. Single-cell RNA-seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell 17, 360–372 (2015).
doi: 10.1016/j.stem.2015.07.013
pubmed: 26299571
pmcid: 8638014
Suh, H. K. et al. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2
doi: 10.1016/j.stem.2007.09.002
pubmed: 18371391
pmcid: 2185820
Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001).
doi: 10.1523/JNEUROSCI.21-18-07153.2001
pubmed: 11549726
pmcid: 6762987
Urban, N. et al. Return to quiescence of mouse neural stem cells by degradation of a pro-activation protein. Science 353, 292–295 (2016).
Bonaguidi, M. A. et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155 (2011).
doi: 10.1016/j.cell.2011.05.024
pubmed: 21664664
pmcid: 3124562
Encinas, J. M. et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579 (2011).
doi: 10.1016/j.stem.2011.03.010
pubmed: 21549330
pmcid: 3286186
Kempermann, G. The pessimist’s and optimist’s views of adult neurogenesis. Cell 145, 1009–1011 (2011).
doi: 10.1016/j.cell.2011.06.011
pubmed: 21703445
Pilz, G. A. et al. Live imaging of neurogenesis in the adult mouse hippocampus. Science 359, 658–662 (2018).
Katsimpardi, L. & Lledo, P. M. Regulation of neurogenesis in the adult and aging brain. Curr. Opin. Neurobiol. 53, 131–138 (2018).
doi: 10.1016/j.conb.2018.07.006
pubmed: 30077888
Ben Abdallah, N. M., Slomianka, L., Vyssotski, A. L. & Lipp, H. P. Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol. Aging 31, 151–161 (2010).
doi: 10.1016/j.neurobiolaging.2008.03.002
pubmed: 18455269
Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).
doi: 10.1523/JNEUROSCI.16-06-02027.1996
pubmed: 8604047
pmcid: 6578509
Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419 (2019).
doi: 10.1016/j.cell.2019.01.040
pubmed: 30827680
Ziebell, F., Dehler, S., Martin-Villalba, A. & Marciniak-Czochra, A. Revealing age-related changes of adult hippocampal neurogenesis using mathematical models. Development 145, dev153544 (2018).
pubmed: 29229768
pmcid: 5825879
Ahn, S. & Joyner, A. L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005).
doi: 10.1038/nature03994
pubmed: 16208373
Blomfield, I. M. et al. Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells. Elife 8, e48561 (2019).
doi: 10.7554/eLife.48561
pubmed: 31552825
pmcid: 6805120
Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics 19, 477 (2018).
doi: 10.1186/s12864-018-4772-0
pubmed: 29914354
pmcid: 6007078
Dumitru, I., Neitz, A., Alfonso, J. & Monyer, H. Diazepam binding inhibitor promotes stem cell expansion controlling environment-dependent neurogenesis. Neuron 94, 125–137 (2017).
doi: 10.1016/j.neuron.2017.03.003
pubmed: 28343864
Berg, D. A. et al. A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell 177, 654–668 (2019).
doi: 10.1016/j.cell.2019.02.010
pubmed: 30929900
pmcid: 6496946
Yuzwa, S. A. et al. Developmental emergence of adult neural stem cells as revealed by single-cell transcriptional profiling. Cell Rep. 21, 3970–3986 (2017).
doi: 10.1016/j.celrep.2017.12.017
pubmed: 29281841
La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).
doi: 10.1038/s41586-018-0414-6
pubmed: 30089906
pmcid: 6130801
Bergen, V. & et al. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. https://doi.org/10.1038/s41587-020-0591-3 (2020).
Hochgerner, H., Zeisel, A., Lonnerberg, P. & Linnarsson, S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Nat. Neurosci. 21, 290–299 (2018).
doi: 10.1038/s41593-017-0056-2
pubmed: 29335606
Yang, C. P., Gilley, J. A., Zhang, G. & Kernie, S. G. ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development 138, 4351–4362 (2011).
doi: 10.1242/dev.065540
pubmed: 21880781
pmcid: 3177307
Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).
doi: 10.1038/nature11689
pubmed: 23201681
Gut, G., Herrmann, M. D. & Pelkmans, L. Multiplexed protein maps link subcellular organization to cellular states. Science 361, eaar7042 (2018).
Zweifel, S. et al. HOPX defines heterogeneity of postnatal subventricular zone neural stem cells. Stem Cell Rep. 11, 770–783 (2018).
doi: 10.1016/j.stemcr.2018.08.006
Bonaguidi, M. A., Song, J., Ming, G. L. & Song, H. A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Curr. Opin. Neurobiol. 22, 754–761 (2012).
doi: 10.1016/j.conb.2012.03.013
pubmed: 22503352
pmcid: 3415562
Pilz, G. A. et al. Functional imaging of dentate granule cells in the adult mouse hippocampus. J. Neurosci. 36, 7407–7414 (2016).
doi: 10.1523/JNEUROSCI.3065-15.2016
pubmed: 27413151
pmcid: 6705545
R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. https://igraph.org/ (2017).
Picardo, M. A. et al. Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus. Neuron 71, 695–709 (2011).
doi: 10.1016/j.neuron.2011.06.018
pubmed: 21867885
pmcid: 3163067
Csardi, G. & Nepusz, T. The igraph software package for complex network research. Int. J. Complex Syst. 1695, 38 (2006).
Kolde, R. pheatmap: Pretty Heatmaps. R package, version 1.0.8. https://CRAN.R-project.org/package=pheatmap (2015).
Jaeger, B. N. et al. Miniaturization of Smart-seq2 for single-cell and single-nucleus RNA sequencing. STAR Protoc. 1, 100081 (2020).
doi: 10.1016/j.xpro.2020.100081
pubmed: 33000004
pmcid: 7501729
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
doi: 10.1093/bioinformatics/bts635
pubmed: 23104886
McCarthy, D. J., Campbell, K. R., Lun, A. T. & Wills, Q. F. Scater: pre-processing, quality control, normalization and visualization of single-cell RNA-seq data in R. Bioinformatics 33, 1179–1186 (2017).
doi: 10.1093/bioinformatics/btw777
pubmed: 28088763
pmcid: 5408845
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019).
doi: 10.1016/j.cell.2019.05.031
pubmed: 31178118
pmcid: 6687398