Dias nummer 1

1
Neuroregeneration
Bear M. F., Connors B. W. Paradiso M. A.
Neuroscience. Exploring the brain. 2007, 3d
ed. Lippincott Williams and Wilkins
2
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

3
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

4
Terminology

• NEURODEGENERATION

The loss of neuronal processes (axons and
dendrites) and death of nerve cells

• NEURODEGENERATIVE DISORDER

A type of neurological disease marked by the loss
of nerve cells e.g. Alzheimers disease (AD),
Parkinsons disease PD), Huntingtons disease (HD)

• REGENERATION

• Growth anew of lost tissue or destroyed parts or
  organs

• NEUROREGENERATION

• Regeneration of the nervous tissue manifested by
• Nerve (axon) regeneration
• Neural stem-cell proliferation, migration and
  differentiation

5
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

6
Axon regeneration

• Traumatic injury of the spinal cord that
  transects axon processes
• results in permanent functional impairment,
  even when the neuronal
• cell bodies that are located away from the
  injury site remain alive.

• At present there are no clinical treatments
  available to stimulate
• regeneration of cut axons within the CNS.

• Although many CNS neurons can survive for years
  after axotomy, the
• severed axons ultimately fail to regenerate
  beyond the lesion site, in
• contrast to those in the PNS or embryonic
  nervous system.

• Spinal cord injured patients receive high doses
  of the steroid
• methylprednisolone immediately following
  injury to suppress an
• unfavorable inflammatory reaction. This drug,
  however, does not
• restore functions that are lost when axons are
  cut.

7
Changes in CNS environment after maturation and
injury
8
Plastic mechanisms potentially contributing to
recovery after spinal cord injury
9
Methods

• In vivo animal models

• In vitro cell cultures

Left neurons were grown on control
fibroblasts Right neurons were grown on
fibroblasts genetically engineered to express CAM
10
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

11
Inhibitors of axon regeneration
Growth inhibitory activity associated with myelin

• Myelin-associated glycoprotein (MAG)

• Growth inhibitory protein Nogo

• Oligodendrocyte-myelin glycoprotein (OMgp)

• Oligodendrocyte-proteoglycan NG2

Growth inhibitory activity present at the glial
scar

• Chondroitin sulfate proteoglycans (CSPG)
• - versican
• - phosphocan
• - neurocan

Other factors limiting axon-regrowth

• Inflammatory response

• Alterations in the ECM

• Upregulation of semaphorins, ephrins, tenascin-C

12
Glial inhibitors
13
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

14
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 signaling responses
- 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.
15
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

16
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.
17
Neural stem cells
Ventricular and subventricular zones in the wall
of the lateral ventricle adjacent to the
caudate-putamen
Subgranular zone of the hippocampus
NSC
Migration of NSC
Olfactory bulb
Differentiation Integration
NSC
Neurons Dentate gyrus
NPC
Differentiation
Local interneurons
18
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
19
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 (blue).
20
Neuroregeneration

• Terminology

• Axon regeneration

• Molecular and cellular mechanisms limiting axon
• regeneration in CNS

• Therapeutic strategies to promote axon
  regeneration

• Neural stem cells

• Stem cell therapy

21
Parkinsons disease
(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 involuntary
movements)
PET scan, dopamine activity in basal ganglia,
putamen and caudate
22
Developmental pathway of dopamine neurons
23
Alternative sources of stem cells for
transplantation in PD
24
Present limitations in the development of the
hESC-based therapy for PD
25
Generation of dopamine neurons from autologous
human mesenchimal stem cells (MSCs)
26
Main points
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.
27
Helpful reading
Blesch A and Tuzhynski MH (2009) Spinal cord
injury plasticity, regeneration and the
challenge of translational drug development. TINS
3241-47. Li J-Y et al. (2008) Lewy bodies in
grafted neurons in subjects with Parkinsons
disease suggest host-to-graft disease
propagation. Nat Medicine 14501-503. Goldman SA
(2007) Disease targets and strategies for the
therapeutic modulation of endogenous neural stem
and progenitor cells. Clin Pharm Therapeutics.
82453-460. Ma QH et al. (2007) Physiological
role of neurite outgrowth inhibitors in
myelinated axons of the central nervous system
implications for the therapeutic neutralization
on neurite outgrowth inhibitors. Curr Pharm Des.
132529-2537. Trzaska KA et al. (2007) Current
advances in the treatment of Parkinson's disease
with stem cells. Curr Neurovasc Res. 499-109.
Yiu G et al. (2006) Glial inhibition of CNS
axon regeneration. Nat Rev Neurosci. 7617-627.
Correia AS et al. (2005) Stem cell-based
therapy for Parkinson's disease. Ann Med.
37487-498. Wang Y et al. (2007) Stem cell
transplantation A promising therapy for
Parkinsons disease. J Neuroimmune Pharmacol.
2243-250.
28
Presentation
http//plab.ku.dk
Professors
Vladimir Berezin
Neuroregeneration