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

Georgios Kalamakis; Daniel Brüne; Srikanth Ravichandran; Jan Bolz; Wenqiang Fan; Frederik Ziebell; Thomas Stiehl; Francisco Catalá-Martinez; Janina Kupke; Sheng Zhao; Enric Llorens-Bobadilla; Katharina Bauer; Stefanie Limpert; Birgit Berger; Urs Christen; Peter Schmezer; Jan Philipp Mallm; Benedikt Berninger; Simon Anders; Antonio del Sol; Anna Marciniak-Czochra; Ana Martin-Villalba

doi:10.1016/j.cell.2019.01.040

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

Georgios Kalamakis
, Daniel Brüne
, Srikanth Ravichandran
, Jan Bolz
, Wenqiang Fan
, Frederik Ziebell
, Thomas Stiehl
, Francisco Catalá-Martinez
, Janina Kupke
, Sheng Zhao
, Enric Llorens-Bobadilla
, Katharina Bauer
, Stefanie Limpert
, Birgit Berger
, Urs Christen
, Peter Schmezer
, Jan Philipp Mallm
, Benedikt Berninger
, Simon Anders
, Antonio del Sol

Anna Marciniak-Czochra, Ana Martin-Villalba

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

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. Aged brains have a small number of highly quiescent neural stem cells that, upon activation, functionally resemble young stem cells; it is the niche itself that becomes more inflammatory and drives this quiescence.

Original language	English
Pages (from-to)	1407-1419.e14
Journal	Cell
Volume	176
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2019.01.040
Publication status	Published - 7 Mar 2019
Externally published	Yes

Funding

We thank S. Wolf from the DKFZ Genomics and Proteomics Core Facility, V. Eckstein from the Heidelberg Universty Hospital FACS Core Facility, Monika Langlotz from the ZMBH FACS Core Facility, Reinhard Gliniorz for technical assistance in performing the comet assay, Gonzalo Saiz-Castro and Klara Zwadlo for technical assistance, Hai-Kun Liu for Tlx-CreER T2 mice, Mathias Heikenwälder for TCF/Lef reporter mice, and the Light Microscopy Core Facility for support. This work was supported by the DFG ( SFB873 , SFB1324 , SFB1036 , INST 161/875-2 ), the Helmholtz Alliance for Aging and Metabolic Programming (AMPro), and the DKFZ . W.F. is supported by the China Scholarship Council . We thank S. Wolf from the DKFZ Genomics and Proteomics Core Facility, V. Eckstein from the Heidelberg Universty Hospital FACS Core Facility, Monika Langlotz from the ZMBH FACS Core Facility, Reinhard Gliniorz for technical assistance in performing the comet assay, Gonzalo Saiz-Castro and Klara Zwadlo for technical assistance, Hai-Kun Liu for Tlx-CreERT2 mice, Mathias Heikenwälder for TCF/Lef reporter mice, and the Light Microscopy Core Facility for support. This work was supported by the DFG (SFB873, SFB1324, SFB1036, INST 161/875-2), the Helmholtz Alliance for Aging and Metabolic Programming (AMPro), and the DKFZ. W.F. is supported by the China Scholarship Council.

Funders	Funder number
Helmholtz Alliance
California Department of Fish and Wildlife	SFB1036, SFB1324, INST 161/875-2, SFB873
Deutsches Krebsforschungszentrum
Horizon 2020 Framework Programme	771376
Deutsche Forschungsgemeinschaft
China Scholarship Council

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Kalamakis, G., Brüne, D., Ravichandran, S., Bolz, J., Fan, W., Ziebell, F., Stiehl, T., Catalá-Martinez, F., Kupke, J., Zhao, S., Llorens-Bobadilla, E., Bauer, K., Limpert, S., Berger, B., Christen, U., Schmezer, P., Mallm, J. P., Berninger, B., Anders, S., ... Martin-Villalba, A. (2019). Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain. Cell, 176(6), 1407-1419.e14. https://doi.org/10.1016/j.cell.2019.01.040

@article{a8eb7dfd3d904bdb90c6061b4c30801c,

title = "Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain",

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. Aged brains have a small number of highly quiescent neural stem cells that, upon activation, functionally resemble young stem cells; it is the niche itself that becomes more inflammatory and drives this quiescence.",

author = "Georgios Kalamakis and Daniel Br{\"u}ne and Srikanth Ravichandran and Jan Bolz and Wenqiang Fan and Frederik Ziebell and Thomas Stiehl and Francisco Catal{\'a}-Martinez and Janina Kupke and Sheng Zhao and Enric Llorens-Bobadilla and Katharina Bauer and Stefanie Limpert and Birgit Berger and Urs Christen and Peter Schmezer and Mallm, \{Jan Philipp\} and Benedikt Berninger and Simon Anders and \{del Sol\}, Antonio and Anna Marciniak-Czochra and Ana Martin-Villalba",

year = "2019",

month = mar,

day = "7",

doi = "10.1016/j.cell.2019.01.040",

language = "English",

volume = "176",

pages = "1407--1419.e14",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

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Kalamakis, G, Brüne, D, Ravichandran, S, Bolz, J, Fan, W, Ziebell, F, Stiehl, T, Catalá-Martinez, F, Kupke, J, Zhao, S, Llorens-Bobadilla, E, Bauer, K, Limpert, S, Berger, B, Christen, U, Schmezer, P, Mallm, JP, Berninger, B, Anders, S, del Sol, A, Marciniak-Czochra, A & Martin-Villalba, A 2019, 'Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain', Cell, vol. 176, no. 6, pp. 1407-1419.e14. https://doi.org/10.1016/j.cell.2019.01.040

TY - JOUR

T1 - Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain

AU - Kalamakis, Georgios

AU - Brüne, Daniel

AU - Ravichandran, Srikanth

AU - Bolz, Jan

AU - Fan, Wenqiang

AU - Ziebell, Frederik

AU - Stiehl, Thomas

AU - Catalá-Martinez, Francisco

AU - Kupke, Janina

AU - Zhao, Sheng

AU - Llorens-Bobadilla, Enric

AU - Bauer, Katharina

AU - Limpert, Stefanie

AU - Berger, Birgit

AU - Christen, Urs

AU - Schmezer, Peter

AU - Mallm, Jan Philipp

AU - Berninger, Benedikt

AU - Anders, Simon

AU - del Sol, Antonio

AU - Marciniak-Czochra, Anna

AU - Martin-Villalba, Ana

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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. Aged brains have a small number of highly quiescent neural stem cells that, upon activation, functionally resemble young stem cells; it is the niche itself that becomes more inflammatory and drives this quiescence.

AB - 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. Aged brains have a small number of highly quiescent neural stem cells that, upon activation, functionally resemble young stem cells; it is the niche itself that becomes more inflammatory and drives this quiescence.

UR - https://www.scopus.com/pages/publications/85061657205

U2 - 10.1016/j.cell.2019.01.040

DO - 10.1016/j.cell.2019.01.040

M3 - Article

SN - 0092-8674

VL - 176

SP - 1407-1419.e14

JO - Cell

JF - Cell

IS - 6

ER -

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

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Funding

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