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Cell. 2019 Mar 7;176(6):1407-1419.e14. doi: 10.1016/j.cell.2019.01.040. Epub 2019 Feb 28.

Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain.

Author information

1
Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany; University of Heidelberg, 69120 Heidelberg, Germany.
2
Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany.
3
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362, Luxembourg.
4
Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
5
Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany; Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing and Bioquant, Heidelberg University, 69120 Heidelberg, Germany.
6
Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing and Bioquant, Heidelberg University, 69120 Heidelberg, Germany.
7
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center, 69120 Heidelberg, Germany.
8
Goethe University Hospital Frankfurt/ZAFES, 60596 Frankfurt, Germany.
9
German Cancer Research Center, Division of Epigenomics and Cancer Risk Factors, 69120 Heidelberg, Germany.
10
Division Chromatin Networks, German Cancer Research Center, 69120 Heidelberg, Germany; Single-cell Open Lab, German Cancer Research Center, 69120 Heidelberg, Germany.
11
Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, 55128 Mainz, Germany; Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; Institute of Psychiatry, Psychology & Neuroscience, Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK; Institute of Psychiatry, Psychology & Neuroscience, MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK.
12
Center for Molecular Biology, Heidelberg University, 69120 Heidelberg, Germany.
13
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362, Luxembourg; CIC bioGUNE, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain; Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia.
14
Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: a.martin-villalba@dkfz-heidelberg.de.

Abstract

The function of somatic stem cells declines with age. Understanding the molecular underpinnings of this decline is key to counteract age-related disease. Here, we report a dramatic drop in the neural stem cells (NSCs) number in the aging murine brain. We find that this smaller stem cell reservoir is protected from full depletion by an increase in quiescence that makes old NSCs more resistant to regenerate the injured brain. Once activated, however, young and old NSCs show similar proliferation and differentiation capacity. Single-cell transcriptomics of NSCs indicate that aging changes NSCs minimally. In the aging brain, niche-derived inflammatory signals and the Wnt antagonist sFRP5 induce quiescence. Indeed, intervention to neutralize them increases activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as a key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.

KEYWORDS:

Wnt signaling; inflammation; interferon; modeling; neural stem cells; quiescence; sFRP5; simulations; single-cell transcriptomics; stem cell aging; subventricular zone

PMID:
30827680
DOI:
10.1016/j.cell.2019.01.040

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