Transcript Regenerating Brain from endogenous stem cells

Regenerating the brain from
endogenous stem cells
AI Ahmed1,2, M Zaben1,2, WP Gray1,2
1Clinical
Neurosciences, University of Southampton and 2Wessex Neurological Centre,
Southampton General Hospital,
Tremona Road,
Southampton,
SO16 6YD
Key events in neural stem cell research
1960s
1970s
1980s
1990s
2000s
The neural stem cell cycle
Neural Stem Cell
SELF RENEWAL
Progenitor Cell
Glioblast
Neuroblast
DIFFERENTIATION
Astrocyte
Oligodendrocyte
Neuron
Neural stem cells have the key characteristics of self renewal and differentiation into all progeny subtypes.
This includes Astrocytes, Oligodendrocytes and Neurons via intermediary progenitor cells.
Stem cell niches
Defined as the microenvironment in which stem cells are found
Influenced by
growth factors, blood vessels, neurons, glia, extracellular matrix
Permissive Niches
Non Permissive niches
Continued birth of neurons in adulthood
No new neurons in adulthood
Two well defined niches
Numerous including
Subgranular zone of dentate gyrus of hippocampus
Subventricular zone
Outer Cortex
Spinal Cord
Amygdala
Striatum
Subventricular zone
Hippocampus
Stem cells in the adult human brain
Initial identification by Eriksson and colleagues1
Patients with terminal cancer given i.v. BRDU which incorporates into
newly born cells
Postmortem analysis reveals BRDU into neurons of dentate gyrus of
hippocampus and subventricular zone
Stem cells identified from surgical specimens both in permissive and non
permissive niches
• the subventricular zone2,3,4
• the periventricular subependymal zone5
• the hippocampus5 (our lab)
• the olfactory bulb6
• the amygdala (our lab)
• the insula cortex (our lab)
Stem cells in the adult human brain (2)
Stem cells isolated from regions distinctly considered non-neurogenic
• the spinal cord7
• the corpus callosum8
• the subcortical white matter9
In summary,
there are cells with stem cell properties throughout the adult
human brain
Understanding the regulatory mechanisms of stem cells
The niche environment influences the stem cell. To manipulate the niche, an
appreciation of the normal physiology is key. In the adult human brain, so far
we can say:
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Stem cells in different regions share common characteristics including proliferation and
self-renewal
cells harboured in the adult human brain have the ability to develop into neurons
cells isolated from human tissue go through steps of morphological and
electrophysiological development towards newly-born functional neurons
Cells expressing stem cell markers give rise to neurons
In animal studies, following targeted controlled cell death with a minimal inflammatory
response, endogenous stem cells can perform a surprising level of anatomical repair
both in permissive (hippocampus) and non-permissive (cortex) areas
Human neural stem cells can be isolated from the adult brain and are capable of
differentiating into functional neurons.
If neurosurgeons are to contemplate using such cells in the treatment of neurological
disorders, providing a source of cells that go on to survive is paramount
The next step
Current therapeutic strategies use fetally derived stem cells for diseases such
as Parkinson’s and spinal cord injury. Results have been disappointing.
In this emerging field of ‘regenerative neurosurgery’, neurosurgeons could be
involved in two distinct approaches to treatment
• Following surgical resection, exogenous stem cells, derived from patients
own cells, are expanded in culture and transplanted back
• We can manipulate the stem cell niche with intrathecal or localised
administration of medication, be it through a single procedure or a
continuous delivery system.
How can a neurosurgeon effect repair?
Strategies to promote CNS repair.
Either
• deployment of exogenous stem cells previously harvested
• manipulation of endogenous stem cells
Placement of drug delivery device
(intrathecal or intraparenchymal
catheter)
Diagnosis of Disease
TBI
SCI
Parkinson’s
Stroke
ALS
in vitro expansion
stereotactic
transplantation
Conclusion
• Stem cells are widespread in the adult human nervous system
• Our understanding of the mechanistic processes is vital to effect repair
• A neurosurgeon is poised to play a critical role in delivering factors or cells
to manipulate the environment, and thus encourage repair
References
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Eriksson, P.S. et al., Neurogenesis in the adult human hippocampus. Nat Med 4 (11), 1313-1317 (1998).
Ayuso-Sacido, A., Roy, N.S., Schwartz, T.H., Greenfield, J.P., & Boockvar, J.A., Long-term expansion of adult
human brain subventricular zone precursors. Neurosurgery 62 (1), 223-229; discussion 229-231 (2008).
Moe, M.C. et al., A comparison of epithelial and neural properties in progenitor cells derived from the
adult human ciliary body and brain. Exp Eye Res 88 (1), 30-38 (2009).
Westerlund, U. et al., Stem cells from the adult human brain develop into functional neurons in culture.
Exp Cell Res 289 (2), 378-383 (2003).
Kukekov, V.G. et al., Multipotent stem/progenitor cells with similar properties arise from two neurogenic
regions of adult human brain. Exp Neurol 156 (2), 333-344 (1999).
Casalbore, P. et al., Tumorigenic potential of olfactory bulb-derived human adult neural stem cells
associates with activation of TERT and NOTCH1. PLoS ONE 4 (2), e4434 (2009).
Dromard, C. et al., Adult human spinal cord harbors neural precursor cells that generate neurons and glial
cells in vitro. J Neurosci Res 86 (9), 1916-1926 (2008).
8. Chojnacki, A., Kelly, J.J., Hader, W., & Weiss, S., Distinctions between fetal and adult human
platelet-derived growth factor-responsive neural precursors. Ann Neurol 64 (2), 127-142
(2008).
9. Nunes, M.C. et al., Identification and isolation of multipotential neural progenitor cells from
the subcortical white matter of the adult human brain. Nat Med 9 (4), 439-447 (2003).