Coordinated Changes in Cellular Behavior Ensure the Lifelong Maintenance of the Hippocampal Stem Cell Population

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Feb 13

PMID 33581058

Citations 64

Authors

Lachlan Harris

Piero Rigo

Thomas Stiehl

Zachary B Gaber

Sophie H L Austin

Maria Del Mar Masdeu

Amelia Edwards

Noelia Urban

Anna Marciniak-Czochra

Francois Guillemot

Affiliations

Soon will be listed here.

Abstract

Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilize during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this stabilization of stem cell numbers in young adults is the result of coordinated changes in stem cell behavior. Although proliferating neural stem cells in juveniles differentiate rapidly, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomics, modeling, and label retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These changes in stem cell behavior result from a progressive reduction in expression of the pro-activation protein ASCL1 because of increased post-translational degradation. These cellular mechanisms help reconcile current contradictory models of hippocampal neural stem cell (NSC) dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species, including humans.

Citing Articles

PTN activity in quiescent neural stem cells mediates Shank3 overexpression-induced manic behavior.

Kim H, Cho B, Kim H, Kang S, An S, Kwon D Nat Commun. 2025; 16(1):2435.

PMID: 40069581 PMC: 11897407. DOI: 10.1038/s41467-025-57699-5.

Neural stem cell heterogeneity in adult hippocampus.

Liang Z, Jin N, Guo W Cell Regen. 2025; 14(1):6.

PMID: 40053275 PMC: 11889326. DOI: 10.1186/s13619-025-00222-4.

Sustaining Brain Youth by Neural Stem Cells: Physiological and Therapeutic Perspectives.

Santos M, Moreira J, Santos S, Sola S Mol Neurobiol. 2025; .

PMID: 39985708 DOI: 10.1007/s12035-025-04774-z.

Restoring carboxypeptidase E rescues BDNF maturation and neurogenesis in aged brains.

Liu H, Jiang D, Yao F, Li T, Zhou B, Zhao S Life Med. 2025; 2(2):lnad015.

PMID: 39872114 PMC: 11749474. DOI: 10.1093/lifemedi/lnad015.

Transcription factor networks in cellular quiescence.

Mitra M, Batista S, Coller H Nat Cell Biol. 2025; 27(1):14-27.

PMID: 39789221 DOI: 10.1038/s41556-024-01582-w.

References

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

Hafemeister C, Satija R . Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 2019; 20(1):296. PMC: 6927181. DOI: 10.1186/s13059-019-1874-1. View

Engler A, Rolando C, Giachino C, Saotome I, Erni A, Brien C . Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone. Cell Rep. 2018; 22(4):992-1002. DOI: 10.1016/j.celrep.2017.12.094. View

Walker T, Kempermann G . One mouse, two cultures: isolation and culture of adult neural stem cells from the two neurogenic zones of individual mice. J Vis Exp. 2014; (84):e51225. PMC: 4131911. DOI: 10.3791/51225. View

Young M, Tye B . Mcm2 and Mcm3 are constitutive nuclear proteins that exhibit distinct isoforms and bind chromatin during specific cell cycle stages of Saccharomyces cerevisiae. Mol Biol Cell. 1997; 8(8):1587-601. PMC: 276178. DOI: 10.1091/mbc.8.8.1587. View

Ziebell F, Dehler S, Martin-Villalba A, Marciniak-Czochra A . Revealing age-related changes of adult hippocampal neurogenesis using mathematical models. Development. 2017; 145(1). PMC: 5825879. DOI: 10.1242/dev.153544. View

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

Knobloch M, von Schoultz C, Zurkirchen L, Braun S, Vidmar M, Jessberger S . SPOT14-positive neural stem/progenitor cells in the hippocampus respond dynamically to neurogenic regulators. Stem Cell Reports. 2014; 3(5):735-42. PMC: 4235138. DOI: 10.1016/j.stemcr.2014.08.013. View

10.

Hagihara H, Toyama K, Yamasaki N, Miyakawa T . Dissection of hippocampal dentate gyrus from adult mouse. J Vis Exp. 2009; (33). PMC: 3142893. DOI: 10.3791/1543. View

11.

Nicola Z, Fabel K, Kempermann G . Development of the adult neurogenic niche in the hippocampus of mice. Front Neuroanat. 2015; 9:53. PMC: 4423450. DOI: 10.3389/fnana.2015.00053. View

12.

Raposo A, Vasconcelos F, Drechsel D, Marie C, Johnston C, Dolle D . Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis. Cell Rep. 2015; 10(9):1544-1556. PMC: 5383937. DOI: 10.1016/j.celrep.2015.02.025. View

13.

Blomfield I, Rocamonde B, Masdeu M, Mulugeta E, Vaga S, van den Berg D . Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells. Elife. 2019; 8. PMC: 6805120. DOI: 10.7554/eLife.48561. View

14.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

15.

Encinas J, Michurina T, Peunova N, Park J, Tordo J, Peterson D . Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 2011; 8(5):566-79. PMC: 3286186. DOI: 10.1016/j.stem.2011.03.010. View

16.

Barker N, Bartfeld S, Clevers H . Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell. 2010; 7(6):656-70. DOI: 10.1016/j.stem.2010.11.016. View

17.

Leeman D, Hebestreit K, Ruetz T, Webb A, McKay A, Pollina E . Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science. 2018; 359(6381):1277-1283. PMC: 5915358. DOI: 10.1126/science.aag3048. View

18.

Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer F . Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy. Cell. 2017; 169(5):807-823.e19. DOI: 10.1016/j.cell.2017.04.018. View

19.

Zhao X, Heng J, Guardavaccaro D, Jiang R, Pagano M, Guillemot F . The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008; 10(6):643-53. PMC: 2680438. DOI: 10.1038/ncb1727. View

20.

Knobloch M, Braun S, Zurkirchen L, von Schoultz C, Zamboni N, Arauzo-Bravo M . Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature. 2012; 493(7431):226-30. PMC: 3587167. DOI: 10.1038/nature11689. View