A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus

Abstract

Continuously generated new neurons promote circuitry plasticity within specialized regions and contribute to specific functions of the adult mammalian brain. A number of recent studies have investigated the cellular origin of adult neurogenesis in the hippocampus, yielding divergent models of neural stem cell behavior. An essential question remains whether these models are overlapping or fundamentally discrete. We review evidence that primary neural precursors in the adult hippocampus exhibit significant heterogeneity in their properties of self-renewal, multi-lineage differentiation and regulation, representing a range from unipotential committed precursors to bona fide self-renewing multipotent neural stem cells. We further present a testable unifying hypothesis of adult neural stem cell behavior in vivo to outline a common framework for future studies of molecular and cellular mechanisms regulating adult neural stem cells and how these cells may contribute to hippocampal function and repair.

Figure 1. Models for neural stem cell (NSC) behavior in the adult hippocampus

(a) Neural lineages according to the radial glia-like cell (RGL) model. RGLs, or Type 1 cells, are quiescent precursors that generate new neurons and astrocytes through intermediate progenitor cell (IPC) and astroglia progenitor phases, respectively. IPCs proliferate while progressively differentiating through multiple stages into neurons, while astroglia progenitors possess comparatively small proliferative capacity. Stage-specific markers are shown for each cell type. Short-term fate-mapping from various cells of origin can be achieved using fluorescent reporter mice under the regulatory control of stage-specific promoters. Long-term indelible lineage-tracing can be performed from various precursors using inducible Cre-LoxP technology in combination with “floxed-on” reporters. The exact cell type to be labeled is controlled by the combination of the CreER driver line, specific reporter line and dose of tamoxifen (Nestin::CreER#: induction with a low dose of tamoxifen). References for each reporter and lineage-tracing mouse line are listed in the Supplementary Information. (b) Three proposed NSC models. In the “Repeated RGL self-renewal” model, RGLs can cycle between quiescent and mitotic states. Once activated, RGLs can divide symmetrically to generate additional RGLs, or asymmetrically to produce neuronal and astroglial lineages. In the “Disposable RGL” model, once activated, RGLs repeatedly divide to generate only the neuronal lineage without returning to quiescence and then terminally differentiate into astrocytes. In the “Nonradial precursor” model, proliferative cells lacking a radial process generate neurons, astrocytes, and even RGLs. Arrows indicate direct cell generation. Dotted arrows represent unknown choices. Double arrows represent multistep cell generation.

Figure 2. A unified NSC model in the adult hippocampus under basal conditions

Multiple precursor subtypes co-exist in the adult dentate gyrus to coordinate tissue homeostasis under basal conditions. Quiescent RGLs undergo three known decisions: (1) Activation; (2) Cell fate choice; and (3) Maintenance/self-renewal. Once exited from quiescence, RGLs can generate new RGLs, nonradial precursors, IPCs and astroglia, but not the oligodendrocyte lineage (2). Afterwards, RGLs can remain in a proliferative state, return to quiescence, or differentiate into an astrocyte (3). While not yet directly observed, a RGL may differentiate into an astrocyte without proliferation (4). Yet to be demonstrated directly, nonradial precursors may generate RGLs and astroglia in addition to the known neuronal generation, while maintaining the precursor state (5). Likewise, NG2 progenitors may choose among proliferation, oligodendrocyte generation and precursor maintenance (6). Importantly, heterogeneity of decisions exists within a single precursor type and ranges from unipotent non-self-renewing progenitors to multipotent self-renewing stem cells. Arrows indicate direct cell generation. Dotted arrows represent potential choices that need further experimental evidence. Double arrows represent multistep cell generation. Arrows with an ‘X’ represent choices not experimentally observed.