Mineyeva, O, Koulakov, A, Enikolopov, G (June 2018) A closer look at the topography of hippocampal neural stem cells indicates their limited self-renewal. Opera Medica et Physiologica, 4. p. 7. ISSN 2500-2287
Abstract
Introduction: Hippocampal neural stem cells (NSCs) are maintained in their niche during the lifetime and can renew themselves through a process of symmetric or asymmetric division. The predominant asymmetric mode of division would lead to a limited renewal and gradual attrition of the stem cell pool, whereas symmetric division mode would lead to addition of new stem cells to the stem cell niche. Both modes have been suggested to occur in the subgranular zone of the dentate gyrus . Possible symmetrical divisions of stem cells are usually inferred from the clonal analysis or from the spatial analysis after labeling with thymidine analogs and focusing on closely residing pairs of labeled NSCs, with an assumption that these pairs of cell retain the label from their common precursor. Both types of analysis also include an assumption of random distribution of stem cells and of their dividing subset. However, it is possible that some of the pairs of closely residing cells appear as a result of close positioning of two unrelated dividing stem cells in the niche space. Therefore, to draw conclusions regarding symmetric divisions of the hippocampal stem cells it is crucial to evaluate the possibility of their non-random distribution and/or activation. Methods: To estimate the frequency of symmetric divisions we took advantage of long-term labeling with BrdU and analyzed the topography of dividing NSCs within all (i.e., both dividing and non-dividing) NSCs in the dentate gyrus of young adult (3 months old) mice. We obtained the xyz positions of all NSCs and of the subset of dividing NSCs by combining a genetic marker (Nestin-driven GFP) and a marker of dividing cells (BrdU). We next determined the distribution of nearest neighbor (NN) distances between cells within the pool of dividing NSCs. We finally compared this distribution of dividing cells with the results of random resampling from a population of all existing NSCs. Further extending this approach, we estimated how random is the result of a continuous age-related disposal of NSCs. To this end, we compared spatial parameters of the stem cell niche of 14 days old and 7 months old mice. Results and conclusions: Instead of estimating the degree of randomness in the distribution of the total set of stem cells and of its dividing subset, we compared the distributions of these sets to each other. Our data show that the distribution of dividing stem cells in adult hippocampus fits the random model that does not imply symmetric cell divisions. In other words, most of the bias observed in the distribution of labeled cells can be accounted for by the bias in the distribution of the entire set of cells. This suggests that some of the previously reports on close positioned pairs of dividing cells in the clonal or division analysis (implying their symmetric division) are in fact due to unaccounted spatial bias, present in the distribution of the entire set of NSCs. Our estimates indicates that at least 85-90% of divisions may be due to asymmetric divisions. We also found that in subregions of dentate gyrus the age-dependent cell elimination is different from random and is biased towards depletion of cell pairs at small distances. Along with recently reported live-imaging data, our findings support the predominance of the asymmetric mode of the hippocampal stem cell division and thus their inability to support or expand the neurogenic reserve. These constraints might be overcome by discovering new agents and stimuli for controlling the modes of stem cell division in the adult brain.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > tissues types and functions > hippocampus organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells |
| CSHL Authors: | |
| Communities: | CSHL labs > Koulakov lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 1 June 2018 |
| Date Deposited: | 24 May 2021 13:02 |
| Last Modified: | 24 Apr 2024 15:10 |
| URI: | https://repository.cshl.edu/id/eprint/40130 |
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