976.3.2.1 Cell-Cell and Cell-ECM Contact
The ECM composition of the SGZ has not been thoroughly investigated so far. In
vitro assays of NSCs isolated from the rat hippocampus have revealed that they are
able to produce their own ECM (laminin, fibronectin) and their adhesion to different
substrates is controlled by integrins (Harper et al. 2010 ). The role of β1-integrin in the
SGZ seems to mimic aspects described during development and in the SEZ. It is nec-
essary for the structural integrity of the niche, for controlling proliferation of NSCs
and for inhibiting astroglial differentiation (Brooker et al. 2016 ). Recent experimental
work also indicated that the large ECM glycoprotein Reelin, which is mostly known
to regulate migration of progenitors (Courtès et al. 2011 ) plays a role in controlling
quiescence of NSCs, but is dispensable for progression into the lineage (Sibbe et al.
2015 ). Finally, it should be noted that the SGZ is a neurovascular niche (Palmer et al.
2000 ), with abundant BVs that offer access to an ECM rich basement membrane.
6.3.2.2 Diffusible Factors
NSCs isolated from the adult hippocampus can be kept in culture in the form of neu-
rospheres (Fig. 6.1) , similar to NSCs of the embryonic brain and of the SEZ. These
cells are kept in medium rich in FGF2 and EGF. Recently, it was found that hippo-
campal NSCs produce their own ciliary neurotrophic factor (CNTF), which pushes
them towards differentiation. In contrast, the presence of FGF2 down- regulates the
expression of CNTF and inhibits spontaneous differentiation in vitro (He et al. 2012 ).
The role of Wnt signalling has been investigated in vitro and in vivo, and the intrigu-
ing finding was that distinct functional outputs were generated depending on whether
the Wnt/β-catenin, or the Wnt/Planar cell polarity pathway was activated. The first is
crucial for cell fate determination and the latter for morphological maturation of neu-
roblasts (Schafer et al. 2015 ). NSCs and their daughter progenitor cells also express
the Wnt receptor Frizzled-1 (FZD1). Conditional knockdown of FZD1 resulted in a
range of defects, including increased astroglial differentiation in expense of neuro-
genesis and increased migration of newborn neurons (Mardones et al. 2016 ). Finally,
interesting results have been generated by investigating BMP signalling in the hip-
pocampal cytogenic niche. Expression of BMP target genes, such as ID3 revealed
low levels of BMP activity in proliferating cells. In addition, overexpression of nog-
gin into granule cells of the dentate gyrus resulted in increased proliferation of NSCs
(Bonaguidi et al. 2008 ). Furthermore, ablation of BMP receptor–II enhanced prolif-
eration and maturation of NSCs and of neuroblasts, whilst overexpression of BMP-4
caused cell cycle exit (Bond et al. 2014 ).
6.3.2.3 Metabolic Regulation
The contribution of hippocampal neurogenesis to learning, memory and mental
health in general has invited high interest in the mechanisms by which the periph-
eral body conditions can be coupled with NSC activity (reviewed in Triviño-Paredes
6 Being a Neural Stem Cell: A Matter of Character But Defined...