PNS and CNS regeneration Flashcards
Intro
- Henry Head experiments
- C-sec shows connective tissue, axons and Schwann cells – very important for transmitting AP (nodes) and PN regrowth – connective tissue sheath of epineuririum and extra-cellular matrix-rich perineurium that surrounds axons and Schwann cells
Pan 2003
- When a PN is severed, axon segment distal to site to cut degenerates, when axon crushed – more rapid recovery occurs because distal damages provide a helpful guide
- Completely severed axons degenerate and remains are cleared by macs – only Schwann in distal stump of nerve and basal lamina components secreted by Schwann cells are available to stimulate and guide regeneration
Debris removal
- After PN cut, axon and Scwhann degenerate – mac take axonal and SC debris triggered by Scwann disintegration
- Deg and reg in idealized single peripheral nerve ‘tube’ of perineurium/basal lamina – once axon is cut, distal portion degenerates and is phagocytosed by macs – after most debris cleared, prox axon stump transformes into a GC, and GC interacts with adjacent SC (in a mouse – nascent GC at site of cut)
- Slow growth cone growth and nerve is re-grown
- Severing a nerve is worse than crushed
- If PN crushed – less scarring and regeneration is more efficient (similar to development – growth cone, crushed = epineurone intact axons recover more quickly)
- SC essential for PN regeneration – once mac cleared debris from degenerating peripheral stump, SC proliferate, express adhesion molecules on their surface and secrete NT and other growth-promoting signaling molecules – in parallel, parent neurone of regenerating axons expresses genes that restore it to a growth state (gene products are often receptors, or signal transduction molecules, allow cell to respond to factors provided by SC
Sabatier 2008
- Activity and use can influence PN axon regrowth
- Ex rats = increase nerve regrowth than sedentary
- If using it = regrowth increases (Hebb and synaptic plasticity)
- Effects of 2 weeks treadmill locomotion on growth of regenerating axons in PN post-injury – common fibular nerves of mice, a subset of axons in PN express yellow fluorescent (YFP) were cut and repaired with allografts with non-fluorescent littermates, and then harvested 2w later
- Mice LINT continuous training (60m), LINT (IT, one group, 10 reps, 20 min total), and high intensity (3 groups, 2, 4 and 10 reps) – 2 reps IT = lowest ex volume, and 60-min CT = highest ex volume
- Axon profiles were significantly longer in control in all ex groups except LINT – CT groups and HINT groups that trained with 4/10 reps axons were more than twice as long as unexercised controls – interval number didn’t impact on elongation
- Axon sprouting enhanced in IT groups but not CT – ex even in small quantities, increases axon elongation in injured peripheral nerves whereas continuous ex resulting in higher vol (total steps) may have no net impact on axon sprouting
Recovery and regeneration
- Neutrophic factors intiate and/or enhance cell survival and axonal regeneration – still needs to find target (in exactly the same way)
- Challenges with transected nerve – NT factor and connect to things then brain and SC ends up rewiring and remodeling (increased plasticity)
- Regeneration of peripheral synapses is essential for recovery – no synapse = no functional circuit so goes elsewhere
- Brachial plexus very complex nerve pattern – head turned and extended shoulder other direction (common injury) – PN regrowth not quite so simple
Sabatier 2009
• modest ex training in injured animals whose PN have been reapired by nerve grafts significantly improves extent of nerve growth
Additional approaches
• Additional approaches – development of biomaterials that substitute lost length of PN and serve as scaffold for migration or differentiation of SC from prox nerve stump to provide replacement nerve sheath (success relies on control of mech forces around injured nerve after repair, minimizing increased activity or training of the injured nerve)
Extracellular matrix molecules in PN
• SC secrete extracellular matrix molecules (laminin, fibronectin, and collagens to provide substrate for growth extension), in response to axon injury (SC secrete N-CAM, LI and N-cadherin on surfaces regenerating axons express complementary cell surface adhesion molecules – SC near site of injury in distal end of nerve increases expression and secretion of a number of NT such as BDNF (crucial for motor axon growth), Trk and P75 NT receptors are elevated following injury on newly generated GC of regenerating peripheral axons, local availability of NT acts to promote ‘growth state’ (trophic effects) for damaged axons as well as defining local target distal to site of damage that direct axon growth (tropic effects)
PNS V CNS
• Recovery in CNS is hindered by glial scarring which blocks axon growth cone
o Oligodendrocytes instead of schwann cells
o Over time microglia and astrocytes released (phagocytes) – phagocytosis = glial scar forms
o GC cannot grow through damaged section (good evidence)
Schwab and Thoenen 1985
• Experimental evidence for regenerative potential of PNS tissue and limited capacity of CNS for regeneration
o Placed SC tissue and sciatic nerve in tissue alongside NGF
♣ Optic nerve = no regrowth
♣ Sciatic nerve = increased regrowth
• Explants of adult/10day old rat sciatic and optic nerves were implanted in culture system + dissociated newborn sympathetic or SN were placed into centre growin in presence of optimal concentrations of NGF
• Electron microscopy showed large axons numbers in sciatic nerve, irrespective of presence and number of living Schwann cells – besides tendency to fasciculate, axons grew with high preference on Schwann cell membranes and Schwann cell side of basal lamina, a situation identical to in vivo regeneration
• Optic nerves – no axons found under any condition
• Points to existence of extremely poor, non-permissive substrate conditions in diff optic nerve which cannot be overcome by strong fibre outgrowth-promoting effects of NGF
So and Aguyao (1985)
• PN environment have growth-promoting capacity for CNS axons as well, experimental animals, severed axons in optic nerve (in periphery but are parts of CNS) or spinal cord can be provided with PN graft that contains SC, basal lamina, and connective tissue components that normally support PNR
Vidal-Sanz 1991
• Central axons grow readily through PN graft, some axons make synapses in target territory to which distal end of graft is connected – experiments show SC define as environment in PN sheath that is particularly well adapted to initiate and support re-growth of damaged adult axons, whether they project to periphery or normally remain in CNS
Barnett and Riddell 2007
- Restoring injured SC function = one of most formidable medical challenges – Glial cell transplantation is widely considered to be one of most promising therapeutic strategies (transplant candidates – SC and OEC’s) – review analyses evidence from animal studies for improved functional recovery following transplantation of OECs into SC injuries, and examine mechs by which repair may be achieved
- Injury models to support view OEC transplants can promote functional recovery, but accumulating anatomical evidence indicates that although axons regenerate within a transplant, they do not cross lesion or reconnect with neurons on opposite side to any significant extent
- Possible neuroprotection and promotion of sprouting of intact fibres are main mechs that contribute to functional recovery - need combination of transplant and synergistic therapies to achieve significant regeneration of axons and re-establish functionally useful connections across SC injury
Raisin 2007
- Damage to NF pathways results in devastating loss of function, due to disconnection of NF from targets – some recovery does occur and this has been correlated with formation of new abnormal connections
- View that untapped growth potential resides in adult CNS has led to attempts to stimulate repair of disconnectional injuries – key factor in failure of axonal regeneration in CNS after injury is loss of aligned glial pathways that NF require for elongation (transplantation of culture adult OEC’s into lesions is being investigated as a procedure to re-establish glial pathways permissive for the regeneration of severed axons
Real-life cases
• Jasper the dog – promising from dragging hind limbs nerve regrowth
o Taken over 20 years to get from cat plasticity dog humans?
• Human evidence – Derek Fidya – no clear evidence with complete SCI (physiologically)
o Clinically complete lesion = some fibres spared
o NG through cyst/excite or promote exisiting neurons
