Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche

Michael P Fatt; Lina M Tran; Gisella Vetere; Mekayla A Storer; Jaclin V Simonetta; Freda D Miller; Paul W Frankland; David R Kaplan

doi:10.1016/j.stemcr.2021.12.010

Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche

Stem Cell Reports. 2022 Feb 8;17(2):259-275. doi: 10.1016/j.stemcr.2021.12.010. Epub 2022 Jan 20.

Authors

Michael P Fatt¹, Lina M Tran², Gisella Vetere³, Mekayla A Storer³, Jaclin V Simonetta⁴, Freda D Miller⁵, Paul W Frankland⁶, David R Kaplan⁷

Affiliations

¹ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
⁴ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada. Electronic address: freda.miller@msl.ubc.ca.
⁶ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Psychology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: paul.frankland@sickkids.ca.
⁷ Program in Neurosciences and Mental Health, Hospital for Sick Children, 18-9716 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: dkaplan@sickkids.ca.

Abstract

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.

Keywords: ABT-263; aging; hippcampus; neural stem cells; neurogenesis; senescence; senescence-associated secretory phenotype; senolytic; spatial memory.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging
Aniline Compounds / pharmacology
Animals
Cell Proliferation / drug effects
Cellular Senescence / drug effects
Cellular Senescence / physiology*
Dentate Gyrus / cytology
Dentate Gyrus / metabolism
Female
Hippocampus / cytology
Male
Mice
Mice, Inbred C57BL
Neural Stem Cells / cytology
Neural Stem Cells / metabolism*
Neurogenesis / drug effects
Spatial Memory / drug effects
Stem Cell Niche / physiology*
Sulfonamides / pharmacology

Substances

Aniline Compounds
Sulfonamides
navitoclax

Abstract

Publication types

MeSH terms

Substances

Grants and funding