A mosaic world: puzzles revealed by adult neural stem cell heterogeneity

Abstract

Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain. The ventricular–subventricular zone (V‐SVZ), adjacent to the lateral ventricles, gives rise to olfactory bulb (OB) neurons, and some astrocytes and oligodendrocytes throughout life. In vitro assays have been widely used to retrospectively identify NSCs. However, cells that behave as stem cells in vitro do not reflect the identity, diversity, and behavior of NSCs in vivo. Novel tools including fluorescence activated cell sorting, lineage‐tracing, and clonal analysis have uncovered multiple layers of adult V‐SVZ NSC heterogeneity, including proliferation state and regional identity. In light of these findings, we reexamine the concept of adult NSCs, considering heterogeneity as a key parameter for analyzing their dynamics in vivo. V‐SVZ NSCs form a mosaic of quiescent (qNSCs) and activated cells (aNSCs) that reside in regionally distinct microdomains, reflecting their regional embryonic origins, and give rise to specific subtypes of OB interneurons. Prospective purification and transcriptome analysis of qNSCs and aNSCs has illuminated their molecular and functional properties. qNSCs are slowly dividing, have slow kinetics of neurogenesis in vivo, can be recruited to regenerate the V‐SVZ, and only rarely give rise to in vitro colonies. aNSCs are highly proliferative, undergo rapid clonal expansion of the neurogenic lineage in vivo, and readily form in vitro colonies. Key open questions remain about stem cell dynamics in vivo and the lineage relationship between qNSCs and aNSCs under homeostasis and regeneration, as well as context‐dependent plasticity of regionally distinct adult NSCs under different external stimuli. WIREs Dev Biol 2016, 5:640–658. doi: 10.1002/wdev.248For further resources related to this article, please visit the WIREs website.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Both the levels of adult neurogenesis, and the destination of newly generated neurons exhibit species-specific differences [17,104]. However, stem cells across phylogeny share a common glial identity and localization.…”

“…The choroid plexus also secretes migratory cues for newly generated neurons [127]. In the V-SVZ, stem cells have a regional identity and give rise to different subtypes of neurons and glia [17]. The diverse array of factors secreted by the LVCP may differentially regulate distinct stem cell pools depending on the combination of receptors they express.…”

MicroRNA‐31 is required for astrocyte specification

“…Ultimately, these cells produce lineage-committed progenitors (glial-restricted, neuron-restricted, astrocyte and oligodendrocyte precursor cells) that give rise to terminally differentiated cells (astroctyes, neurons and oligodendrocytes) (Dietrich et al 2008). In the adult brain, radial glial cells function as NPCs (Alvarez-Buylla et al 2001; Chaker et al 2016; Gallo and Deneen 2014; Maldonado-Soto et al 2014; Namihira and Nakashima 2013; Noctor et al 2001; Paul et al 2017; Tome-Garcia et al 2017). NPCs rely on general stem cell factors such as Lin28, Oct4 and SOX2, and tissue specific factors in order to self-renew (Aloia et al 2013; Loh et al 2006; Ronan et al 2013; Tiwari et al 2013).…”

Concepts toward directing human astroplasticity to promote neuroregeneration

“…Advancements in gene‐expression profiling and tools for functional characterization of adult astrocytes are now succeeding in defining these distinct subtypes of astrocytes (Chai et al, ; John Lin et al, ; Morel et al, ). Even within adult neural stem cells, a potential source of new astrocytes, extensive heterogeneity exists (Chaker et al, ; Dulken et al, ). Whether these regional identities have a significant effect on the response to injury and disease is still unclear, yet it is probable, as they receive signals depending on the type of surrounding local neural circuits that introduce another layer of diversity (including multiple neuronal subtypes, various efferent and afferent connections, and altered ratios of excitatory to inhibitory synapses).…”