Mimicking Neural Stem Cell Niche by Biocompatible Substrates

Abstract

Neural stem cells (NSCs) participate in the maintenance, repair, and regeneration of the central nervous system. During development, the primary NSCs are distributed along the ventricular zone of the neural tube, while, in adults, NSCs are mainly restricted to the subependymal layer of the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. The circumscribed areas where the NSCs are located contain the secreted proteins and extracellular matrix components that conform their niche. The interplay among the niche elements and NSCs determines the balance between stemness and differentiation, quiescence, and proliferation. The understanding of niche characteristics and how they regulate NSCs activity is critical to building in vitro models that include the relevant components of the in vivo niche and to developing neuroregenerative approaches that consider the extracellular environment of NSCs. This review aims to examine both the current knowledge on neurogenic niche and how it is being used to develop biocompatible substrates for the in vitro and in vivo mimicking of extracellular NSCs conditions.

Figure 1

Neural stem cell niche in the early stages of CNS development. (a) During early embryogenesis, neuroepithelial cells transform into radial glial cells (RGCs) with cell process elongating toward the pial surface of the neural tube. RGCs divide asymmetrically to form neuroblasts. (b) Neuroblast division generates progenitors known as “transit-amplifying progenitor cells” (TAPCs), which divide rapidly and generate the first local neural niche or ventricular zone (VZ); at this stage the first blood vessels invade the neural tube from the dorsal region toward the VZ zone and extend their branches tangentially to the pial surface. (c) In the forebrain, TAPC proliferation produces a second germinal zone, the subventricular zone (SVZ). In this zone, postmitotic neuroblasts and glioblasts migrate toward the dorsal intermedia and marginal zones and produce neurons and glial cells. CNS, central nervous system; ECM, extracellular matrix; IZ, intermediate zone; MZ, marginal zone.

Figure 2

Neural stem cell niche in the adult dentate gyrus and subventricular zone. (a) Sagittal section view of an adult rodent brain showing the two main restricted regions where active adult neurogenesis is present, the dentate gyrus in the hippocampal formation and the lateral ventricle, from which type A cells migrate to form the rostral migratory stream (RMS) toward the olfactory bulb. (b) Neural stem cell niche in the subventricular zone (SVZ). Three types of progenitor cells are found close to the ependymal cell layer in the SVZ: a population of radial glia-like cells (type B cells) have the potential to serve as adult neural stem cells (NSCs) and generate transit-amplifying nonradial NSCs (type C cells), which later give rise to neuroblasts (type A cells). The SVZ includes several ECM components (yellow), called fractones (inset), which make contact with all the cell types, including the blood vessels and astrocytes in this region. (c) In the adult subgranular zone (SGZ), a population of radial glia-like cells (type 1 cells), along with nonradial glia-like cells (type 2 cells), generate neuroblasts. These neuroblasts then migrate into the granule cell layer and mature into neurons. CSPG, chondroitin sulfate proteoglycan; FGF2, fibroblast growth factor 2; GCL, granular cell layer; ML, molecular layer.