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7.3 Role of the Neural Stem Cell Niche in the Origin
and Maintenance of Glioblastoma Stem Cells Arising
from Aberrant Stem and Precursor CellsNiches for stem cells are found in various organs in the body and are specific for
each type of stem cell. These niches are not just repositories for stem cells but are
also complex and dynamic ecosystems (Gilbertson and Rich 2007 ; Scheres 2007 ;
Scadden 2006 ). In the brain, stem cells have been found to primarily reside in the
SVZ and SGZ. The niches within SVZ and SGZ consist of heterogeneous cell popu-
lations, extracellular matrix proteins and other secreted proteins. The role of the
stem cell niche within the brain is to regulate the self-renewal and differentiation of
neural stem cells (Gage 2000 ; Merkle et al. 2004 ; Palmer et al. 2000 ).
SVZ, lining the later ventricles in the brain contains slow diving Nestin+/ GFAP+
type B astrocytes (NSCs), which are rapidly dividing type C astrocytes (progenitor
cells) that give rise to type A astrocytes (neuroblasts). Type A astrocytes in turn give
rise to committed neurons upon migrating anteriorly towards olfactory bulb (OB)
(Alcantara Llaguno et al. 2015 ). The astrocytes within these niches are also in close
contact with ependymal cells that line the cavity of the niches and play a role in
preventing the differentiation of cell within the niche by (i) expressing CXCR4 (that
binds to distally secreted SDF-1), (ii) binding to sonic hedgehog (SHH) and (iii) by
secreting factors such as EGF, bFGF, IGF1, TGF-α, VEGF, ephrins (Doetsch 2003 ;
Fidoamore et al. 2016 ). The other main component of SVZ and SGZ is a network of
capillaries that are in close proximity to NSCs. These facilitate bi-directional com-
munication between NSCs and endothelial cells through factors such as BDNF,
VEGFC, PDGF, IL8, IGF-1 and bFGF (Riquelme et al. 2008 ; Leventhal et al. 1999 ;
Ramirez-Castillejo et al. 2006 ). This close proximity to endothelial cells and the
ensuing communication indicates a possibility that there may be amore permeable
BBB within the stem cells niches allowing them access to systemic growth factors,
nutrients and hormones (Fidoamore et al. 2016 ).
The extracellular matrix is yet another important player in regulation of neural
stem cell fate. Studies show that tenascin C has a regulatory effect on NSC fate and
number (Garcion et al. 2004 ; Tavazoie et al. 2008 ). Heparin sulfate proteoglycans
(HSPs) have been shown to interact with BMP-2-2, HH, Wnts and other morpho-
gens crucial in adult neurogenesis. HSPs have also been shown to interact with
tenascin C, collagens, laminins, VEGF, EGF, FGFs, IGF-II, PDGF-AA, chemo-
kines and cytokines (Doetsch 2003 ). NOTCH signaling which is an important para-
crine signaling mechanism for regulating proliferation and differentiation of NSCs
is also altered in GSCs, helping GSCs maintain an undifferentiated stem-like cell
state. GSCs have been shown to lose oncogenic potential when NOTCH and its
ligands Delta-like1 and Jagged-like-1 are downregulated (Stockhausen et al. 2009 ;
Louvi and Artavanis-Tsakonas 2006 ; Fan et al. 2010 ). In addition, neuronal signals
from ChAT+ (Choline acetyltransferase) neurons present within the SVZ, microglia
and cerebrospinal fluid could also regulate NSC proliferation and differentiation
(Paez-Gonzalez et al. 2014 ). These studies indicate the highly sophisticated and
A. Sattiraju et al.