Neuroregeneration Bear M. F., Connors B. W. Paradiso M. A. Neuroscience. Exploring the brain. 2007, 3d ed. Lippincott Williams and Wilkins Neuroregeneration Terminology Axon regeneration Molecular and cellular mechanisms limiting axon regeneration in CNS
Bear M. F., Connors B. W. Paradiso M. A. Neuroscience. Exploring the brain. 2007, 3d ed.
Lippincott Williams and Wilkins
The loss of neuronal processes (axons and dendrites) and death of nerve cells
A type of neurological disease marked by the loss of nerve cells: e.g. Alzheimer’s disease (AD), Parkinson’s disease PD), Huntington’s disease (HD)
Changes in CNS environment after maturation and injury
Plastic mechanisms potentially contributing to recovery
after spinal cord injury
Left: neurons were grown on control fibroblasts
Right: neurons were grown on fibroblasts genetically engineered to express CAM
Inhibitors of axon regeneration
Growth inhibitory activity associated with myelin
Growth inhibitory activity present at the glial scar
Other factors limiting axon-regrowth
Strategies to promote axon regeneration
1. Neutralization of the inhibitory factors in the injured CNS
- Ab infusion (MonAb, IN-1, against Nogo-A )
- A therapeutic vaccine approach
- Passive immunization at the time of lesion
- Antagonist peptide (Nogo-66 NEP1-40 peptide)
- Inhibition of Rho signaling (Y-27632, an inhibitor of p160ROCK)
- Inhibiting CSPG (Chondroitinase ABC)
- Anti-scarring treatment (inhibition of fibroblast proliferation)
2. Stimulation of axon regeneration by modulating the neuronal
- Treatment with neurotrophic factors (NGF, BDNF, NT-3,
GDNF, LIF, FGF-2)
3. Cell transplantation: e.g. Schwann cells, fibroblasts modified to
express trophic factors, fetal spinal cord transplants, embryonic
stem cells etc.
Neural stem cells
Neurodegenerative disorders (AD, PD and HD) are characterized
by continuous loss of neurons that are not replaced.
It is postulated that a primary deficit in neural cell proliferation,
migration and differentiation might contribute to net cell loss and
neuronal circuit disruption in these disorders.
Neural stem cells
Ventricular and subventricular zones
in the wall of the lateral ventricle
adjacent to the caudate-putamen
zone of the
Migration of NSC
Neural stem cell niches
The SVZ niche, cell types
and stem cell lineage
The DG neurogenic niche,
cell types and lineage
SVZ, subventricular zone; DG, dentate gyrus; LV, lateral ventricle; BL, specialized
basal lamina; BV, blood vessels; A (red), neuroblasts; B (blue), neural stem cells
(SVZ astrocytes); C (green), transit rapidly amplifying cells; D (yellow), precursors;
G (red), neurons
Stem and progenitor cells in the adult human brain
The human temporal lobe: it includes periventricular neural stem cells (red) that generate at least
three populations of potentially neurogenic transit amplifying progenitors of both neuronal and
glial lineages (yellow). These include the neuronal progenitor cells of the ventricular subependyma,
those of the SGZ of the dentate gyrus, and the glial progenitor cells of the subcortical white matter.
Each transit amplifying pool may then give rise to differentiated progeny appropriate to their
locations, including neurons (purple), oligodendrocytes (green), and parenchymal astrocytes
Substantia nigra pars compacta
(degenerative disorder of the CNS that often impairs the sufferer's motor skills and speech)
PD patient (sketch, 1886)
Muscle rigidity, tremor (bradykinesia)
Treatment: L-DOPA ( dyskinesia:
PET scan, dopamine activity in
basal ganglia, putamen and caudate
Developmental pathway of dopamine neurons
Alternative sources of stem cells for transplantation in PD
Present limitations in the development of the hESC-based therapy for PD
Generation of dopamine neurons from autologous human mesenchimal stem cells (MSCs)
Neural degeneration in the central nervous system is manifested by the loss of neuronal processes (axons
and dendrites) and death of nerve cells resulting in dysfunctional plasticity and cognitive impairment.
Traumatic injury of the spinal cord that transects neuronal processes results in permanent functional
impairment, even when the neuronal cell bodies that allocated away from the injury site remain alive.
The glial environment in the adult CNS, which includes inhibitory
molecules in CNS myelin as well as proteoglycans associated with astroglial scaring, might present a major
hurdle for successful axon regeneration.
Therefore, targeting the inhibitory components of the adult glial environment might not only promote the
regeneration of the damaged nerve fibers but also enhance axon sprouting and plasticity after CNS injury.
Neural stem cells, able to self renew and give rise to both neurons and glia, line the cerebral ventricles of
the adult human brain. These various stem and progenitor cell types may provide targets for
pharmacotherapy for a variety of disorders of the central nervous system. Each resident progenitor type
may be immortalized and induced to differentiate in vivo by the actions of both exogenous factors and
small molecule, modulators of progenitor selective signaling pathways.
Stem cell transplantation to replace the degenerated neurons may be a promising therapy for PD.
There are three sources of stem cells currently in testing: embryonic stem cell, neural stem cells and
mesenchymal stem cells. Future stem cell research should focus not only on ameliorating the symptoms
of PD, but also on neuroprotection or neural rescue that can favorably modify the natural course and
slow the progression of the disease.