Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain

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, Frederick

AU - Stiehl, Thomas

AU - Catalá-Martínez, 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 P

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 indicated 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 increased activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.

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 indicated 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 increased activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.

KW - Wnt signaling

KW - inflammation

KW - interferon

KW - modeling

KW - neural stem cells

KW - quiescence

KW - sFRP5

KW - simulations

KW - single-cell transcriptomics

KW - stem cell aging

KW - subventricular zone

UR - http://www.scopus.com/inward/record.url?scp=85061657205&partnerID=8YFLogxK

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 -