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of cells contacting the CC (described above). Using a GFAP-GFP transgenic mice
line, Sabourin et al. ( 2009 ) showed that the majority of neurosphere forming cells
are dorsally located GFAP+ cells lying ependymally and subependymally that
extend radial processes toward the pial surface. A posterior study also claimed that
GFAP-expressing cells lining the CC participate to the generation of multipotent
neurospheres in vitro. However, they showed restricted self-renewal properties
compared with GFAP-negative ependymal-derived neurospheres or GFAP-
expressing neural stem cells from the SVZ (Fiorelli et al. 2013 ).
Taken together, the remarkable multipotent stem cell properties of spinal cord
ependymal cells outside their niche make them an attractive source for the replace-
ment of glia and neurons lost after injury or neurodegenerative diseases. The precise
identity of the cell population with highest in vitro stemness within the spinal cord
ependymal niche remains controversial and future work needs to be done to solve
this problem.
5.7 Regulation of the CC Stem Cell Niche
Stem cells in neurogenic niches of the adult brain are regulated by a plethora of fac-
tors such as age and activity (Kempermann 2008 ), hormones (Lucassen et al. 2008 )
and neurotransmitters (Jang et al. 2008 ). The decrease of neurogenesis with age in
mammals seems to be related with the decline of the activity of progenitor cells via
distinct mechanisms in the SVZ and the hippocampus (Molofsky et al. 2006 ;
Hattiangady and Shetty 2008 ). Similarly, the mitotic activity of spinal ependymal
cells gradually declines as the animal ages to stop about 9 weeks after birth (Sabourin
et al. 2009 ). The molecular mechanisms of the proliferation halt during early post-
natal life in this spinal stem cell niche has not been yet unveiled.
During embryogenesis, the biology of progenitors and newborn cells is tightly
regulated by activity via the action of diverse neurotransmitter systems (Ben-Ari
and Spitzer 2010 ; Wang and Kriegstein 2009 ). Progenitors in adult stem cell niches
in the brain have been shown to be regulated by γ-amino butyric acid (GABA),
glutamate, acetylcholine, dopamine, serotonin and nitric oxide (Jang et al. 2008 ). In
the SVZ for example, GABA released from newborn neurons inhibits the prolifera-
tion of neighboring progenitors making a feedback control system to adjust neuro-
genesis to functional demands (Lo Turco et al. 1995 ; Haydar et al. 2000 ; Liu et al.
2005 ). Although less is known about this kind of regulation in spinal stem cell
niches, a similar set of neurotransmitters -either produced by cellular components
of the niche or by surrounding axonal fibers- may influence the behavior of
CC-contacting progenitors (Reali et al. 2011 ; Corns et al. 2013 , 2015 ; Marichal
et al. 2016 ). Both in low vertebrates and mammals, progenitor-like cells in the ependyma
(Fig. 5.2a) are surrounded by CSFcNs which have the molecular signature of imma-
ture neurons (expression of DCX and PSA-NCAM) and synthetize GABA
(Fig. 5.2b; Roberts et al. 1995 ; Stoeckel et al. 2003 ; Reali et al. 2011 ). In addition,
GABAergic terminals are present around the CC (Fig. 5.2a; Trujillo-Cenóz et al. 2007 ;
N. Marichal et al.