INT 94JY Getting New Brain Cells: Neurogenesis in the Adult Brain

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INT 94JY Getting New Brain Cells Neurogenesis in
the Adult Brain Seminar 7 Neural stem cell
therapeutics for neurodegeneration
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Papers

• Reflections Paper (20)
• Describe what you learned in this course.
• Discuss what you liked, what you did not, and
  what you would have liked to hear (more or less)
  about.
• 3 pages maximum due last day of seminar (Dec. 5).

• Please get to me by Dec 15th
• kippin_at_psych.ucsb.edu
• Psych East main office (first floor) or 2821.

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Neurological Disorders Stem Cell Therapies

• Parkinsons disease (PD) loss of brain stem
  dopamine neurons that drive the basal ganglia
  (striatium) input to motor cortex.
• Huntingtons disease (HD) loss of GABA neurons
  in basal ganglia (striatium).
• Alzheimers disease (AD) loss of acetylchoine
  neurons in basal forebrain.
• Stroke anoxia induced brain damage.
• Traumatic injury blunt force damage to brain or
  spinal cord.

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From stem cell to function
Only differentiated neurons are able to fulfill
the functional aspects of the brainneed to get
from therapeutic cell to neurons.
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

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Fetal Tissue and NSCs

• Developing nervous system contains cells with NSC
  characteristics but these cells either
• loose capability to act as NSCs
• or
• NSCs migrate back to subventricular zone

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Transplant fetal tissue.
Dopamine-containing fetal brain stem tissue
transplanted into Parkinsons Disease patients
increase dopamine levels.
Freed et al 2001
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Transplant fetal tissue.
Control patients
Transplant patients
Unified Parkinsons Disease Rating Scale.
Fetal tissue transplants decrease PD symptoms
particularly in younger patients.
Freed et al 2001
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Transplant fetal tissue.
Fetal transplant increase metabolism and
attenuate HD deficits (variable results).
Bachoud-Levi et al., 2006
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

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Transplantation of Adult NSCs for spinal cord
damage.
Matrix of extracellular components is implant to
provide structural support for hNSC transplant
into rodents.
http//www.pnas.org/cgi/content/full/052678899/DC1
Teng et al 2002
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Transplantation of Adult NSCs
http//www.pnas.org/cgi/content/ full/052678899/DC
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Have functional recovery with transplant.
Teng et al 2002
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hNSC for primate model of PD.

• Redmond et al 2007 hNSC into primate model of PD
  (SN lesion).

hNSC implanted into SN incorporated into
surrounding cirucit and sent projection (axons)
to striatum and produced functional recovery!!!
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

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Transplantion of ESCs

• Engineered ESC transplants produce more DA
  neurons and increase recover from DA-lesion
  deficits (actually produce over-compensation

Kim et al., 2002
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

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Stimulation of Endogenous NSCs
Proliferation (EGF) and survival/differentiation
(EPO) factors allow tissue repair and reverses
deficits produced by stroke.
Kolb et al. 2006
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Stimulation of Endogenous NSCs
EGF EPO produced tissue is critical for
functional recovery.
Kolb et al. 2006
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

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Transplantion of growth factor releasing NSCs
GDNF produced by transplanted hNSCs increase size
of DA cells (but not numbers).
Behrstock et al. 2006
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Transplantion of growth factor releasing NSCs
GDNF releasing hNSCs reverse DA-lesion deficits.
Behrstock et al. 2006
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Stem Cell Strategies for Treatment of
Neurodegenerative Diseases

• Transplant fetal tissue.
• Transplant neural stem cells (NSCs).
• Transplant embryonic stem (ES) cells.
• Stimulate endogenous neural stem cells.
• Transplant growth factor producing cells.

There are currently many viable strategies for
promoting recovery of function from brain damage.
Now, we have to determine which works best for a
particular type of brain damage, including
producing minimal side effects.