Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Onur Basak; Teresa G. Krieger; Mauro J. Muraro; Kay Wiebrands; Daniel E. Stange; Javier Frias-Aldeguer; Nicolas C. Rivron; Marc van de Wetering; Johan H. van Es; Alexander van Oudenaarden; Benjamin D. Simons; Hans Clevers

doi:10.1073/pnas.1715911114

Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Onur Basak, Teresa G. Krieger, Mauro J. Muraro, Kay Wiebrands, Daniel E. Stange, Javier Frias-Aldeguer, Nicolas C. Rivron, Marc van de Wetering, Johan H. van Es, Alexander van Oudenaarden, Benjamin D. Simons^*, Hans Clevers^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67(iresCreER) allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

Original language	English
Pages (from-to)	E610-E619
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1715911114
Publication status	Published - 23 Jan 2018

Keywords

neural stem cells
cellular dynamics
modeling
single
cell sequencing
ki67
ADULT SUBVENTRICULAR ZONE
SELF-RENEWAL
VASCULAR NICHE
LINEAGE PROGRESSION
SUBEPENDYMAL ZONE
SONIC HEDGEHOG
NEUROGENESIS
REVEALS
SIGNALS
PROTEIN
Lateral Ventricles/cytology
Cell Proliferation
Transcriptome
Neurogenesis
Receptors, Tumor Necrosis Factor/metabolism
Single-Cell Analysis
Stem Cell Niche
Cell Lineage
Animals
Mice
Neural Stem Cells/physiology

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10.1073/pnas.1715911114Licence: CC BY

Cite this

Basak, O., Krieger, T. G., Muraro, M. J., Wiebrands, K., Stange, D. E., Frias-Aldeguer, J., Rivron, N. C., van de Wetering, M., van Es, J. H., van Oudenaarden, A., Simons, B. D., & Clevers, H. (2018). Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy. Proceedings of the National Academy of Sciences of the United States of America, 115(4), E610-E619. https://doi.org/10.1073/pnas.1715911114

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title = "Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy",

abstract = "The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67(iresCreER) allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.",

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author = "Onur Basak and Krieger, {Teresa G.} and Muraro, {Mauro J.} and Kay Wiebrands and Stange, {Daniel E.} and Javier Frias-Aldeguer and Rivron, {Nicolas C.} and {van de Wetering}, Marc and {van Es}, {Johan H.} and {van Oudenaarden}, Alexander and Simons, {Benjamin D.} and Hans Clevers",

year = "2018",

month = jan,

day = "23",

doi = "10.1073/pnas.1715911114",

language = "English",

volume = "115",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Basak, O, Krieger, TG, Muraro, MJ, Wiebrands, K, Stange, DE, Frias-Aldeguer, J, Rivron, NC, van de Wetering, M, van Es, JH, van Oudenaarden, A, Simons, BD & Clevers, H 2018, 'Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 4, pp. E610-E619. https://doi.org/10.1073/pnas.1715911114

TY - JOUR

T1 - Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

AU - Basak, Onur

AU - Krieger, Teresa G.

AU - Muraro, Mauro J.

AU - Wiebrands, Kay

AU - Stange, Daniel E.

AU - Frias-Aldeguer, Javier

AU - Rivron, Nicolas C.

AU - van de Wetering, Marc

AU - van Es, Johan H.

AU - van Oudenaarden, Alexander

AU - Simons, Benjamin D.

AU - Clevers, Hans

PY - 2018/1/23

Y1 - 2018/1/23

N2 - The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67(iresCreER) allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

AB - The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67(iresCreER) allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

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KW - cellular dynamics

KW - modeling

KW - single

KW - cell sequencing

KW - ki67

KW - ADULT SUBVENTRICULAR ZONE

KW - SELF-RENEWAL

KW - VASCULAR NICHE

KW - LINEAGE PROGRESSION

KW - SUBEPENDYMAL ZONE

KW - SONIC HEDGEHOG

KW - NEUROGENESIS

KW - REVEALS

KW - SIGNALS

KW - PROTEIN

KW - Lateral Ventricles/cytology

KW - Cell Proliferation

KW - Transcriptome

KW - Neurogenesis

KW - Receptors, Tumor Necrosis Factor/metabolism

KW - Single-Cell Analysis

KW - Stem Cell Niche

KW - Cell Lineage

KW - Animals

KW - Mice

KW - Neural Stem Cells/physiology

U2 - 10.1073/pnas.1715911114

DO - 10.1073/pnas.1715911114

M3 - Article

SN - 0027-8424

VL - 115

SP - E610-E619

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 4

ER -