83guanosine triphosphatase–activating protein (called ARHGAP11B) has been sin-
gled out as a gene expressed only in human RGCs that has possibly contributed to
their distinct behaviour as compared to mouse RGCs (Florio et al. 2015 ).
On the other hand, it is obvious that even the very primitive NSCs (meaning
either those found in early animal species, or those operating during early embry-
onic stages of neurogenesis) do not behave in similar ways, exhibiting fundamen-
tally different repertoires of neurogenesis, as dictated by the available genetic
information and cues from the micro-environment. NSCs isolated from the adult
mouse brain are still in a stage of genetic and epigenetic flexibility that allows them
to revert to an ESC behaviour once implanted in the blastocyst microenvironment
(Clarke et al. 2000 ), or to generate directly blood cells when exposed to the appro-
priate cues (Bjornson et al. 1999 ). In contrast, human glial progenitors grafted in the
mouse hippocampus generate astrocytes that exhibit the human morphology, irre-
spective of the overwhelming mouse tissue environment (Han et al. 2013 ). The
interplay between intrinsic and extrinsic cues in controlling the behaviour of NSCs
can be clearly seen in ex vivo experimental assays. When mouse NSCs are cultured
in growth factor-rich conditions as free-floating cells, they tend to generate 3D
aggregates called neurospheres (Fig. 6.1). These are essentially amorphous com-
plexes consisted of multipotent progenitors and more differentiated cells of neuro-
nal and glial fate. When the same cells are cultured on 3D scaffolds, again in growth
factor-rich conditions and under appropriate rotor spin, they generate microscopic
brains (Camp et al. 2015 ; Qian et al. 2016 ).
In this chapter, we will focus mostly on the microenvironment of NSCs, describ-
ing the main cellular and extracellular elements with which NSCs are in direct or
indirect contact throughout the different stages of their life: from embryonic devel-
opment to the mature CNS as well as in cases of disease, especially during tumori-
genesis. Whenever possible, we will also refer to the functional significance of these
micro-environmental cues. The larger volume of information is derived from studies
in rodents (mostly mice and rats); however, whenever available, information will be
given for the human NSCs and for other model organisms. Before continuing, a
reference should be made to the concept of the NSCs as “builders” of their micro-
environment. NSCs have the extraordinary ability to perform significant aspects of
their cell-generation program in vitro, and when operating in vivo they built the
nervous system with a minimal contribution from other tissues (such as adipose,
bone and connective tissue, or muscles). These observations suggest that NSCs
combine the ability to perform a sophisticated program of symmetric and asymmet-
ric divisions, with strictly controlled progression towards fate commitment, and to
produce, at the same time, basic elements of the tissue, such as the extracellular
matrix (ECM). Indeed, embryonic and adult NSCs gradually create and maintain a
tissue populated almost exclusively by their daughter cells that -besides neurons-
include cells exhibiting a range of structural, nutritional and even tissue-clearing
activity (Lovelace et al. 2015 ). In parallel, NSCs synthesize basic ECM compo-
nents, such as laminins and Tenascin-C (Kazanis et al. 2007 , 2010 ; Lathia et al.
2007 ) and single-cell transcriptome analysis in mouse and human NSCs has revealed
their ability to control self-renewal in an autocrine way (Pollen et al. 2015 ).
6 Being a Neural Stem Cell: A Matter of Character But Defined...