L17 - Regeneration in the Mature Nervous System Flashcards
Why is regeneration important?
Large number of traumatic injuries in peripheral nerves Spinal cord injury Traumatic brain injury Stroke Loss of neurones in disease
Regeneration in Xenopus
Tadpole tail regeneration triggered by BMP’s
Critical period where regeneration can occur
Regeneration in Salamander
Schwann cells migrate to the blastoma and help with regrowth
Regeneration in Worm
Can regrow whole anterior and posterior regions
Nerve structure
Axon surrounded by myelin sheath made of Schwann cells
These form into a fascicle surrounded by endoneurium and perineurium
Nerve injuries - axonotmesis
Axon divided but connective tissue layers maintained
Nerve injuries - neurotmesis
Axon and connective tissue layers divided
Peripheral nerve regeneration
Cell death more likely closer to soma
Proximal axon and soma – reorganisation and re-expression of immature features
- E.g. tubulins
Distal axon – Wallerian degeneration
Denervated muscle
Muscle atrophy
AChR reversal to embryonic
MUSK increase
External electrical input can help prevent atrophy
What does regeneration involve?
Mitosis and rearrangement of Schwann cells
Formation of Bands of Bungner - rows of Schwann cells to guide axon
Re-growth along dividing Schwann cells
Sprouting – neighbouring cells help reverse damage
What is disrupted in crush injuries?
Basal lamina and ECM intact
- Better regrowth and accuracy
What is disrupted in cut injuries?
Basal lamina and ECM disrupted
Regeneration in CNS
Spinal cord injuries
Regeneration in the brain
Transplants and stem cell
Spinal cord injuries
Sprouting followed by failed regeneration and degeneration
Cysts and glial scars form
Recovery of connections difficult
Inhibitory myelin
CNS neurons avoid oligodendrocytes in vitro Removing myelin / oligos improves regeneration
Autoimmunisation to myelin proteins ↑ regeneration
Name of myelin protein that inhibits axon growth?
Nogo-a
Nogo family
Nogoa - 200kd - oligodensrocytes and developing neurons
Nogob - 55kd - many cells
Nogoc - 25kd - muscle
Fish and salamanders lack?
Nogo-a
Nogo knockout?
Partially decreases inhibition
Antibodies against nogo?
Improves regeneration in spinal cord
Motor recovery
Partial lesions fairly recoverable - associated with sprouting of remaining fibres
In humans takes several months
Nogo –a suppression improves recovery in rat models
Objections to NOGO
No correlation between nogo / receptor level and regenerative capacity
Transplanted hippocampal neurons grow axons into myelin
Much myelin is removed by macrophages after damage
Regeneration is poor in grey matter too
Astrocytes
Responsible for poor regeneration
Found in CNS not PNS
Astrocytes proliferate at lesions
Glial scar
Jumbled astrocytes
Attachment to astrocytes impairs regeneration
Secrete inhibitory condroitin sulphate proteoglycan - CSPG’s
Repair - spinal cord bridges
Biological and artificial
Filled with growth factors, ECM, synthetic matrix
Repair - transplant foetal cells
Parkinson’s
- Undesired side-effects
- New trial promising with better defined material
Huntington’s
- Graft survival but little integration or improvement
Repair - transplant
Human embryonic stem cell derived progenitors - preparing clinical trial for Parkinson’s
Umbilical cells
Autologous NS stem cells
Stem cell dividing neural precursors found in?
Adult vertebrate brain
Fish and amphibia retina
Example of regeneration
Male songbirds
- SVZ → High vocal centre
Mammalian forebrain SVZ and dentate gyrus
- Hippocampus and olfactory epithelium
Olfactory ensheating cells
Wrap olfactory axon bundles
Early reports - spinal cord regeneration not consistent
Mixtures of OEC’s with basal cells can?
Produce new neurons
