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 journalArticleAcademicpeer-review

72 Citations (Web of Science)

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 languageEnglish
Pages (from-to)E610-E619
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number4
DOIs
Publication statusPublished - 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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