Embryonic neural stem cells.
The entire vertebrate nervous system
develops from a simple neuroepithelium. Early in development
comprises a single cell layer, and cells within it can be defined as
neural stem cells as they divide both to self-renew and to produce
differentiated progeny. Initally they divide symmetrically to produce two
daughter neural stem cells and so expand the stem cell population. Later
in development they switch to asymmetrical divisions producing neurones
and then glia. Neural stem cells are polarized cells, with processes
contacting both the pial and ventricular surfaces of the developing CNS.
Both these contacts are maintained as the neuroepithelium thickens during
development with the generation of neurones, with the stem cells now
adopting a radial glial phenotype.
The behaviour of the stem cells is
controlled by a multitude of factors, both intrinsic and extrinsic,
epigenetic regulation, growth factors, cell-cell contacts and cell-matrix
interactions. Our work is focussed on the latter two, specifically the
roles of the adhesion molecules cadherins, integrins and extracellular
matrix. We have shown that tenascin-C is required for normal development
of neural stem cells in vivo (Garcion Development 2004). Neural stem
cells also express high levels of integrins and we have demonstrated that
these can be used to sort and enrich for neural stem cells in both human
and rodent cells (Campos Development 2004, Hall Stem Cells 2006).
Laminins are highly expressed around neural stem cells (Lathia J Comp
Neurol 2007) and promote the growth of human neural stem cells when added
to the culture medium (Hall BMC Neurosci 2008), while integrins control
the proliferation and survival of progenitor cells. Current work funded
by the MRC and the BBSRC continues our investigations into the roles of
integrins and tenascin-C in both the mouse and chicken embryo, using
knock-out mice, blocking antibodies and RNA intereference to investigate
the effects of removing cell/matrix interactions.
Adult neural stem cells.
Neural stem cells in the adult CNS are
localized to restricted regions (often called “niches”) including that
adjacent to the lateral ventricle (the subependymal zone or SEZ). In
light of our results showing expression and function of extracellular
matrix and integrin receptors in embryonic neural stem cells, we have
examined the role of these molecules in adult SEZ stem cells. Tenascin-C
is highly expressed, but surprisingly we find that mice lacking tenascin-C
show no perturbation of stem cell function as evidenced by normal
regeneration of transit amplifying cells and neuroblasts following their
ablation with anti-mitotic drugs. Currently, in work funded by an NIH
Quantum grant and in collaboration with colleagues at Baylor, Rice and the
NIMR, Mill Hill, we are documenting the expression of laminins and their
receptors in the SEZ and asking how changes in these molecules following
injuries such as stroke contribute to the increased (but ineffective)
neurogenesis that occurs. The long term goal of these experiments is to be
able to design and engineer artificial microenvironments that support
adult neural stem cells and can be transplanted into regions of the CNS
that might otherwise be unable to contribute to the repair process.