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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E610-E619. doi: 10.1073/pnas.1715911114. Epub 2018 Jan 8.

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

Author information

1
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands.
2
Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 GC, Utrecht, The Netherlands.
3
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom.
4
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229ER, Maastricht, The Netherlands.
5
Princess Máxima Centre, 3584 CT, Utrecht, The Netherlands.
6
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom; bds10@cam.ac.uk h.clevers@hubrecht.eu.
7
Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0HE, United Kingdom.
8
Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
9
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands; bds10@cam.ac.uk h.clevers@hubrecht.eu.

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 Ki67iresCreER 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.

KEYWORDS:

cellular dynamics; ki67; modeling; neural stem cells; single-cell sequencing

PMID:
29311336
PMCID:
PMC5789932
DOI:
10.1073/pnas.1715911114
[Indexed for MEDLINE]
Free PMC Article

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