Non-monotonic Changes in Progenitor Cell Behavior and Gene Expression during Aging of the Adult V-SVZ Neural Stem Cell Niche

Abstract

Summary: Neural stem cell activity in the ventricular-subventricular zone (V-SVZ) decreases with aging, thought to occur by a unidirectional decline. However, by analyzing the V-SVZ transcriptome of male mice at 2, 6, 18, and 22 months, we found that most of the genes that change significantly over time show a reversal of trend, with a maximum or minimum expression at 18 months. In vivo, MASH1+ progenitor cells decreased in number and proliferation between 2 and 18 months but increased between 18 and 22 months. Time-lapse lineage analysis of 944 V-SVZ cells showed that age-related declines in neurogenesis were recapitulated in vitro in clones. However, activated type B/type C cell clones divide slower at 2 to 18 months, then unexpectedly faster at 22 months, with impaired transition to type A neuroblasts. Our findings indicate that aging of the V-SVZ involves significant non-monotonic changes that are programmed within progenitor cells and are observable independent of the aging niche. : Temple and colleagues show through a multi-time-point study that age-associated changes in gene expression and cell behavior in the adult V-SVZ are predominantly non-monotonic. While neurogenesis declines with aging, the number and cell division rate of transit-amplifying progenitor cells declines to 18 months and then surprisingly increases between 18 and 22 months. Furthermore, they demonstrate that these behaviors are recapitulated in single progenitor cells growing in clonal culture, indicating that age-associated changes are programmed and niche independent. Keywords: subventricular zone, aging, neural stem cells, lineage analysis