Quiescent Neural Stem Cells for Brain Repair and Regeneration: Lessons from Model Systems

The adult mammalian brain harbours quiescent neural stem cells (NSCs), which possess a latent capacity to generate neurons and glia. Mechanistic insights into the origins and functional properties of quiescent NSCs are starting to arise in rodents, Drosophila, and regenerative vertebrates. It is becoming apparent that NSCs undergo different types of quiescence, such as G0 and G2 quiescence, or resting and dormant quiescence. Environmental signals, such as exercise or feeding, might increase the activation of quiescent NSCs. Putative trajectories from quiescence to activation have been reconstructed bioinformatically from single-cell transcriptome data. In general, quiescent NSCs are restricted to producing specific neuron subtypes after activation in vivo. It is possible to modify these outputs experimentally in some instances. The ability to control the outputs of quiescent NSCs will be an essential step in harnessing them for brain repair. Neural stem cells (NSCs) are multipotent progenitors that are responsible for producing all of the neurons and macroglia in the nervous system. In adult mammals, NSCs reside predominantly in a mitotically dormant, quiescent state, but they can proliferate in response to environmental inputs such as feeding or exercise. It is hoped that quiescent NSCs could be activated therapeutically to contribute towards repair in humans. This will require an understanding of quiescent NSC heterogeneities and regulation during normal physiology and following brain injury. Non-mammalian vertebrates (zebrafish and salamanders) and invertebrates (Drosophila) offer insights into brain repair and quiescence regulation that are difficult to obtain using rodent models alone. We review conceptual progress from these various models, a first step towards harnessing quiescent NSCs for therapeutic purposes. Neural stem cells (NSCs) are multipotent progenitors that are responsible for producing all of the neurons and macroglia in the nervous system. In adult mammals, NSCs reside predominantly in a mitotically dormant, quiescent state, but they can proliferate in response to environmental inputs such as feeding or exercise. It is hoped that quiescent NSCs could be activated therapeutically to contribute towards repair in humans. This will require an understanding of quiescent NSC heterogeneities and regulation during normal physiology and following brain injury. Non-mammalian vertebrates (zebrafish and salamanders) and invertebrates (Drosophila) offer insights into brain repair and quiescence regulation that are difficult to obtain using rodent models alone. We review conceptual progress from these various models, a first step towards harnessing quiescent NSCs for therapeutic purposes. a border that separates the brain from the systemic circulation that enables oxygen, nutrients, and hormones to pass into the brain while restricting the entry of pathogens. In mammals, endothelial cells, astrocyte endfeet and pericytes contribute to barrier function. In Drosophila and basal vertebrates such as sharks the barrier is composed of glia. in rodent studies, enriched environment paradigms often refer to greater cage space and introduction of objects that promote exploration and interaction, including toys, ladders, platforms, tunnels, and a wider variety of food. These animals have a heightened social experience relative to rodents reared under standard laboratory conditions, but are still relatively deprived compared to those in the wild. characterization of progeny cells through clonal labelling and lineage analysis. transplantation of cells or tissues from their normal location to an ectopic one. a high-fidelity pathway to repair double-stranded DNA lesions that can only operate during S/G2 phases because it requires a homologous repair template. Outside S/G2, DNA lesions are repaired by the lower fidelity non-homologous end-joining pathway, which can introduce nucleotide insertions and/or deletions. a subdivision of the vertebrate brain that has important functions in homeostasis, feeding, growth, and general metabolism; the hypothalamus was recently discovered to be a third site of adult neurogenesis in rodents. an assay to identify non-dividing or rarely dividing cells. Cells are pulse labelled (e.g., through brief exposure to BrdU or transient expression of a fluorescent protein) and are then subjected to a long chase period, often of several weeks to months. Rapidly dividing cells dilute their label at each cell division, whereas non-dividing and rarely dividing cells maintain high levels of labelling. Label-retaining cells include quiescent cells but also, for example, cells that underwent terminal differentiation after incorporating the label. a mouse strain that exhibits faster and more complete, scar-free, tissue repair in response to wounding (e.g., ear hole punch) compared to common laboratory mouse strains. The mechanisms underlying this heightened regenerative capacity are not well understood. commonly used to infer proliferation, these include BrdU (5-bromo-2′-deoxyuridine) and EdU (5-ethynyl-2′-deoxyuridine), and are often delivered orally, by injection, or through incubation. Thymidine analogues incorporate into DNA during S phase or during DNA repair and can be detected using antibodies or covalent labelling kits. a division of the Drosophila melanogaster central nervous system that is located posterior to the brain lobes. The ventral nerve cord is convenient to access due to its proximity to the ventral surface of the animal. The mechanisms that pattern the dorsal–ventral axis of the ventral nerve cord are evolutionarily conserved in the mammalian spinal cord.