Increased Re-Entry into Cell Cycle Mitigates Age-Related Neurogenic Decline in the Murine Subventricular Zone§

Authors

  • Elizabeth A. Stoll,

    Corresponding author
    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
    2. Graduate Program in Neurobiology & Behavior,University of Washington, Seattle, Washington, USA
    • University of Washington, 815 Mercer St., Box 358056, Seattle, Washington 98195-8056, USA
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    • Telephone: 206-897-5717

  • Behnum A. Habibi,

    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
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  • Andrei M. Mikheev,

    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
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  • Jurate Lasiene,

    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
    2. Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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  • Susan C. Massey,

    1. Department of Applied Mathematics,University of Washington, Seattle, Washington, USA
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  • Kristin R. Swanson,

    1. Department of Pathology,,University of Washington, Seattle, Washington, USA
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  • Robert C. Rostomily,

    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
    2. Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
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  • Philip J. Horner

    Corresponding author
    1. Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
    2. Graduate Program in Neurobiology & Behavior,University of Washington, Seattle, Washington, USA
    3. Department of Neurological Surgery, University of Washington, Seattle, Washington, USA
    • Institute for Stem Cell & Regenerative Medicine,University of Washington, Seattle, Washington, USA
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    • Telephone: 206-897-5715; Fax: 206-685-1357


  • Author contributions: E.A.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, development of mathematical model, and manuscript writing; B.A.H.: collection and/or assembly of data and data analysis and interpretation; A.M.M.: conception and design; J.L.: collection and/or assembly of data; S.C.M. and K.R.S.: development of mathematical model; R.C.R. and P.J.H.: conception and design, financial support, data analysis and interpretation, and manuscript writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS September 10, 2011.

Abstract

Although new neurons are produced in the subventricular zone (SVZ) of the adult mammalian brain, fewer functional neurons are produced with increasing age. The age-related decline in neurogenesis has been attributed to a decreased pool of neural progenitor cells (NPCs), an increased rate of cell death, and an inability to undergo neuronal differentiation and develop functional synapses. The time between mitotic events has also been hypothesized to increase with age, but this has not been directly investigated. Studying primary-cultured NPCs from the young adult and aged mouse forebrain, we observe that fewer aged cells are dividing at a given time; however, the mitotic cells in aged cultures divide more frequently than mitotic cells in young cultures during a 48-hour period of live-cell time-lapse imaging. Double-thymidine-analog labeling also demonstrates that fewer aged cells are dividing at a given time, but those that do divide are significantly more likely to re-enter the cell cycle within a day, both in vitro and in vivo. Meanwhile, we observed that cellular survival is impaired in aged cultures. Using our live-cell imaging data, we developed a mathematical model describing cell cycle kinetics to predict the growth curves of cells over time in vitro and the labeling index over time in vivo. Together, these data surprisingly suggest that progenitor cells remaining in the aged SVZ are highly proliferative. STEM CELLS 2011;29:2005–2017.

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