Lecture 6: Brain Cell Replacement Strategies Flashcards
What are some of the ways stem cells might be used to treat brain diseases?
-Cell replacement (replace dead/damaged cells in the brain)
-Promoting plasticity
-Delivery of therapeutic proteins (use stem cells to cross blood brain barrier).
-Disease modeling and drug discovery
What are some general cell replacement strategies for type 1 diabetes?
Think of this in terms of peripheral disease
Type 1 diabetes: loss of beta cells in the pancreas that produce insulin
Use stem cells to make new beta cells, transplant them, and restore insulin production
What are some general cell replacement strategies for heart attacks?
Heart attack: cardiomyocytes die from a lack of oxygen.
Fix the vascular supply with bypass surgery, stent etc, and then transplant new stem cell derived cardiomyocytes
It’s been shown that when these stem cells differentiate they spontaneously contract.
Is it possible to have cell replacement strategies in the brain?
Maybe, but it is harder because neurons need to interconnect to produce behavior movement, thought, etc.
One possible focus: Parkinson’s disease
Describe the symptoms of Parkinson’s disease.
Characterized by motor impairment.
Tremor, rigidity, slowed movements, shuffling steps, freezing.
2nd or 3rd most common disease after AD and dementia
What causes PD?
Caused by degeneration of dopamine producing neurons in the substantia nigra (black substance) (produces neuromelanin) (located deep in the brain).
The axons of these dopaminergic neurons project to and connect with neurons in the striatum (caudate and putamen).
You have to lose ___ of the dopamine producing neurons before symptoms of PD appear.
70%
Reduced levels of the neurotransmitter ___ causes many of the symptoms of PD.
dopamine
Describe cell replacement strategies in the brain for PD.
-Replace dopaminergic neurons
1) Make dopaminergic neurons or precursors from stem cells.
2) Transplant cells that can survive and mature into dopaminergic neurons
3) Have neurons grow axons to the target (striatum)
4) Form appropriate synaptic connections with target neurons.
(1 and 2 are the main focus)
(3 and 4 are difficult to do)
What is an issue with cell replacement strategies in the brain for PD?
Cells don’t grow and connect the same way when transplanted so this poses an issue for the efficacy and potential side effects
How can we promote and guide axonal growth?
One strategy to induce axonal outgrowths to provide a source of neurotrophins in the target region.
Neurotrophins can be both trophic (survival promoting) and tropic (directing axonal outgrowth).
Better yet: create a gradient of neurotrophins or other trophic molecules similar to the gradients that occur during brain development.
May also need to develop a biomaterial scaffold to help guide axonal growth toward the striatum (highway for axons)
Will cell replacement strategies be easier or harder for other brain disorders?
Harder!
AD= atrophy all around lots of different types of neurons are dying.
TBI= depends heavily on severity of injury, messy areas/damage
What is synaptic plasticity?
Hebb: When an axon of cell A is near enough to excite cell B repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency as one of the cells firing B is increased.
Dr. Shatz: Cells that fire together, wire together; Neurons that are out of synch, loose their link
What is one way to measure synaptic plasticity?
LTP
Electrically stimulate one set of cells or axons and then record the electrical response in the cells that receive signals (axonal innervation) from them.
Long term potentiation (LTP) is a long lasting increase in the response of the downstream neurons. It tells you that those synaptic connections have been strengthened.
LTP may provide a cellular mechanism for memory formation, both are triggered rapidly, last for months, require protein synthesis, and involve the association of stimuli.
LTP is associated with ____ and ___ at the postsynaptic site.
1) increased production
2) localization of receptors
Requires protein synthesis
Likely long term memory.
