Neural stem cell niches in health and diseases

Abstract

Presence of neural stem cells in adult mammalian brains, including human, has been clearly demonstrated by several studies. The functional significance of adult neurogenesis is slowly emerging as new data indicate the sensitivity of this event to several "every day" external stimuli such as physical activity, learning, enriched environment, aging, stress and drugs. In addition, neurogenesis appears to be instrumental for task performance involving complex cognitive functions. Despite the growing body of evidence on the functional significance of NSC and despite the bulk of data concerning the molecular and cellular properties of NSCs and their niches, several critical questions are still open. In this work we review the literature describing i) old and new sites where NSC niche have been found in the CNS; ii) the intrinsic factors regulating the NSC potential; iii) the extrinsic factors that form the niche microenvironment. Moreover, we analyse NSC niche activation in iv) physiological and v) pathological conditions. Given the not static nature of NSCs that continuously change phenotype in response to environmental clues, a unique "identity card" for NSC identification is still lacking. Moreover, the multiple location of NSC niches that increase in diseases, leaves open the question of whether and how these structures communicate throughout long distance. We propose a model where all the NSC niches in the CNS may be connected in a functional network using the threads of the meningeal net as tracks.

Fig. (1)

Distribution of GFAP immunoreactivity in adult rat brain GFAP expression is visualized by immunofluorescence using chicken anti-GFAP antibodies (Abcam, dil. 1: 1000). The image is reconstructed from collection of high-resolution confocal microscopy images. Boxes show high magnifications of the regions with highest levels of immunoreactivity: striatum, lateral ventricular zone and the glia limitans. Bright field histological section stained by H&E.

Fig. (2)

Distribution of SOX2 immunoreactivity in adult rat brain Map of SOX2 expression (red) in adult rat brain by anti-Sox2 goat antibodies (Santa Cruz, dil. 1: 1000]. Image reconstructed from collection of high-resolution confocal microscopy images. Boxes show high magnification of dentate gyrus of the hippocampus and hypothalamus, external border of the cortex.

Fig. (3)

Distribution of nestin immunoreactivity in adult rat brain Map Nestin expression in adult rat brain visualized by mouse anti-rat Nestin antibodies (BD Bioscience, dil. 1: 1000] (green): As for Figs. (1 and 2), this image is reconstructed from collection of high-resolution confocal microscopy images. Nestin distribution shows regions with high expression levels of this NSC marker. Note the frequent association of nestin immunoreactivity with bona fide vessels of the parenchyma. Boxes show high magnifications of lateral ventricular zone, external border of the cortex, dentate gyrus of the hippocampus and hypothalamus.

Fig. (4)

NSC niche network hypothesis NSC niches have been described in many region of the adult brain, including sub ventricular zone, hippocampus, cerebral cortex, olfactory bulb, retina, spinal cord and meninges. The niches may exist as individual entities or as a network of niches. Data on responses of niches to physiological, pharmacological and pathological stimulation suggest that niches form a network, possibly centered on the SVZ that may act as the “reservoir” of the brain NSCs. The red lines highlight well established connections between niches. Meninges may have a dual role: they are both one of the niches of the network and the anatomical branches of the net sustaining connection between niches and NSC migration to sites of integration into the normal tissue.