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Cell Rep. 2018 Dec 18;25(12):3231-3240.e8. doi: 10.1016/j.celrep.2018.11.088.

Increasing Neural Stem Cell Division Asymmetry and Quiescence Are Predicted to Contribute to the Age-Related Decline in Neurogenesis.

Author information

1
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Mathematics, Chair of Mathematical Modeling of Biological Systems, Technische Universität München, Garching, Germany.
2
Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiological Genomics, Ludwig-Maximilians University Munich, Munich, Germany. Electronic address: fcalzola@uni-mainz.de.
3
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
4
Institute of Stem Cell Research, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Physiological Genomics, Ludwig-Maximilians University Munich, Munich, Germany; Department for Cell Biology and Anatomy, Biomedical Center of LMU, Ludwig-Maximilians University Munich, Munich, Germany. Electronic address: ninkovic@helmholtz-muenchen.de.
5
Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. Electronic address: carsten.marr@helmholtz-muenchen.de.

Abstract

Adult murine neural stem cells (NSCs) generate neurons in drastically declining numbers with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline are unresolved issues. We therefore clonally traced NSC lineages using confetti reporters in young and middle-aged adult mice. To understand the underlying mechanisms, we derived mathematical models that explain observed clonal cell type abundances. The best models consistently show self-renewal of transit-amplifying progenitors and rapid neuroblast cell cycle exit. In middle-aged mice, we identified an increased probability of asymmetric stem cell divisions at the expense of symmetric differentiation, accompanied by an extended persistence of quiescence between activation phases. Our model explains existing longitudinal population data and identifies particular cellular properties underlying adult NSC homeostasis and the aging of this stem cell compartment.

KEYWORDS:

adult neurogenesis; computational model; lineage tracing; lineage tree simulation; model averaging; moment equations

PMID:
30566852
DOI:
10.1016/j.celrep.2018.11.088
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