Neuronal Regeneration and Neural Stem Cells Flashcards
What is the ability to regenerate determined by?
the availability of neurotrophic factors and the presence of an intrinsic growth program
What is the ability to regenerate countered by?
the presence of growth inhibitors in the glial scar and myelin
What happens after SCI?
many cells die immediately as well as progressively
What happens after penetrating injury?
cells from the PNS often invade the injury site to form a connective tissue scar that incorporates astrocytes, progenitor cells and microglia
What happens during the early stages of injury?
myelin-associated inhibitors from intact oligodendrocytes and myelin debris can restrict axon regrowth
What does the recruitment of inflammatory cells and reactive astrocytes over time lead to?
the formation of a glial scar, often accompanied by a fluid-filled cyst
What is the scarring process associated with?
the increased release of chondroitin sulphate proteoglycans, which can further limit regeneration
What is Nogo-A?
a neurite growth inhibitor that plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the CNS of higher vertebrates
What are the 3 types of factor that regulate neurite outgrowth?
- permissive e.g. ECM-associated, CAMs, neurotrophic factors
- inhibitory e.g. Nogo
- guiding e.g. ephrins, Slits
What are the 2 main molecular inhibitors of the adult CNS glial environment?
- CSPGs associated with reactive astrocytes from the glial scar
- myelin-associated inhibitors from intact oligodendrocytes and myelin debris
What does signalling from the Nogo-66 receptor do?
affect the actin cytoskeleton through activation of RhoA
What does a reduction of myelin-associated inhibitors do?
enhance regeneration
What does the end of severed nerve in the extracellular space between cells in a wounded spinal cord do?
form a growth cone which explores the territory by constantly forming and retracting filopodia
What does the extracellular space between cells in a wounded spinal cord contain?
- CSPG molecules, which have a backbone and many side branches that block the way
- special cell-membrane-anchored proteins that actively stop growing nerve fibres
What does the bacterial enzyme ChABC do?
prune the side chains of CSPGs, clearing the way for growing nerve fibres and promote regeneration of corticospinal tract axons
What does intrathecal treatment with ChABC degraded CS-GAG at the injury site do?
- upregulate a regeneration-associated protein in injured neurons
- promote regeneration of both ascending sensory projections and descending corticospinal tract axons
What do embryonic neurons have for regeneration?
a cell-intrinsic program leading to axonal elongation
What is the intrinsic growth capacity of adult CNS and PNS neurons respectively?
- CNS = limited
- PNS = high
What does a conditioning lesion do?
protect axons from degeneration after a second injury
What is the DRG neuron model for CNS axonal regeneration?
- young DRG CNS axons could regenerate, but adult ones could not
- regeneration of the CNS branch of the DRG neuron could be enhanced by a conditioning lesion to the PNS branch
- cAMP could mimic the effects of a conditioning lesion, overcoming even the inhibitory effects of myelin-associated inhibitors
What is the relationship between cAMP levels and regenerative ability?
decreased cAMP levels = decreased ability
What does neurotrophin treatment do?
elevate cAMP levels
What is PTEN?
a tumour suppressor phosphatase whose deletion enhances axonal regeneration
What does PTEN act as?
a brake for the mTORC1 pathway, which promotes potent CNS axon regeneration
