Abstract

The modes of stem cell divisions (e.g., symmetric vs. asymmetric) can have a profound impact on the number of progeny and tissue growth, repair, and function. This is particularly relevant for adult neural stem cells, since stem cell-derived neurons affect cognitive and mental states, resistance to stress and disease, and response to therapies. Here we show that although dividing stem cells in the adult hippocampus display a certain bias towards paired distribution (which could imply the prevalence of symmetric divisions), this bias already exists in the distribution of the general population of stem cells and may be responsible for the perceived occurrence of symmetric stem cell divisions. Remarkably, the bias in the distribution of stem cells decreases with age. Our results argue that the preexisting bias in stem cell distribution may affect current assumptions regarding stem cell division and fate as well as conjectures on the prospects of brain repair and rejuvenation.

Highlights

  • IntroductionProduction of new adult neurons starts with the activation and division of resident neural stem cells[1,2,3]

  • New neurons are continuously generated in selected regions of the adult brain

  • A relevant question is not whether close positioning of two dividing stem cells is different from random positioning, but whether it is different from the distribution pattern of the entire population of stem cells; i.e., it is critical to determine whether any non-random spatial bias in the distribution of dividing cells reflects a pre-existing bias in the distribution of their precursors

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Summary

Introduction

Production of new adult neurons starts with the activation and division of resident neural stem cells[1,2,3] In the hippocampus, these stem cells are located in a narrow region (subgranular zone, SGZ) of the dentate gyrus (DG). Adult stem cells are marked by a long radial process that traverses the granule cell layer (GCL) and terminates with an arbor of fine processes in the molecular layer (ML) These cells can be identified directly, through examination of the expression of specific markers, application of viral labeling, or the use of transgenic reporter lines; they can be identified indirectly, e.g., through lineage tracing or clonal analysis. Our model sets forth asymmetric divisions as the prevalent mode of stem cell division in the adult hippocampus This model implies the gradual depletion of the stem cell pool. Our results call for a critical reevaluation of the current paradigms regarding symmetric vs. asymmetric divisions of stem cells (whether probed by DNA labeling or by clonal analysis) and, by extension, of stem cell loss due to aging and disease, as well as for a reassessment of the prospects of brain rejuvenation

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