Heterogeneity of Adult Neural Stem Cells

Adult neurogenesis mainly happens in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. The hippocampus is an important part of the brain. In the adult hippocampus, new granule cells made from neural stem cells (NSCs) become part of existing neural circuits and are directly involved in cognitive functions, learning, and memory. The adult NSCs population is not uniform; it has multiple subpopulations with different functions and shapes. Understanding the differences among NSCs is crucial for learning how tissue-specific stem cells and adult neurogenesis work.

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Overview of Neural Stem Cell Heterogeneity

Recently, Weixiang Guo's team published a review article entitled "Neural Stem Cell Heterogeneity in Adult Hippocampus" in Cell Regeneration, which comprehensively discussed the origin, regional distribution, morphology, and molecular characteristics of adult NSCs in the hippocampus, especially the molecular mechanism of the balance between activation and quiescence of NSCs. and heterogeneity of morphological and molecular features, especially the molecular mechanisms underlying the balance between the activated and quiescent states of NSCs. The in-depth understanding of the heterogeneity of neural stem cells provides new cellular and molecular regulatory ideas for neural development, adult neurogenesis, and nerve regeneration and repair.

The developmental provenance of adult NSCs remains under active investigation, with current understanding centred around three principal origin models: sequential, set-aside, and continuous. The sequential hypothesis posits a defined temporal progression wherein embryonic NSCs first generate neurons, subsequently glial cells, before ultimately transitioning into the adult NSC state. Contrastingly, the set-aside model proposes an early bifurcation during embryonic development; within niches such as the SVZ, one NSC contingent actively produces neurons and glia, while a distinct subpopulation enters protracted quiescence, persisting until adulthood. A more recent continuous model highlights Hoxp-positive NSCs residing in the SGZ; these progenitors are suggested to maintain continuous production of diverse terminal cell lineages from mid-embryogenesis (E11.5) throughout postnatal life, eventually shifting to a quiescent state after birth.

The establishment and fate decisions of these NSC populations are intricately regulated by conserved signalling pathways, notably Wnt and Sonic Hedgehog (Shh). Differential responsiveness to these signals delineates functionally distinct hippocampal NSC subtypes. Axin2-positive NSCs, modulated by Wnt signalling, are characterized by active self-renewal dynamics. Conversely, Gli1-positive NSCs respond to Shh signalling and predominantly adopt a quiescent state, a characteristic rendering them potentially more susceptible to age-related changes and extrinsic perturbations. Consequently, elucidating the distinct origins and regulatory networks governing adult NSC subpopulations represents a formidable yet crucial endeavour for a comprehensive understanding of adult neurogenesis.

Significant heterogeneity is also evident in the regional distribution and behaviour of adult NSCs. For instance, dorsal hippocampal NSCs typically exhibit higher proliferative activity compared to their ventral counterparts, and neurons generated from these dorsal precursors display accelerated maturation trajectories. Such pronounced regional variations in NSC function may be orchestrated by underlying molecular gradients within the hippocampal niche, potentially involving factors like sfrp3 that differentially modulate dorsal versus ventral NSC activity.

Fig.1 Different morphologies of adult neural stem cells in the SGZ region of the hippocampus.¹

Furthermore, morphological diversity contributes another layer of complexity to the adult NSC pool. Observed phenotypes include horizontal and radial orientations, as well as distinct α-, β-, and Ω-type morphologies. Critically, these structural variations are not merely descriptive; they correlate with specific functional attributes and lineage potentials, thereby underscoring the profound heterogeneity inherent to adult neural stem cells.

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Reference

1. Liang, Ziqi, Nuomeng Jin, and Weixiang Guo. "Neural stem cell heterogeneity in adult hippocampus." Cell Regeneration 14.1 (2025): 6. Distributed under Open Access license CC BY 4.0, without modification.