Regeneration of Spinal Axons in Lower Vertebrates

Regeneration of Spinal Axons in Lower Vertebrates

Regeneration and repair of the central nervous system Stuart Bunt Dept of Anatomy and Human Biology, UWA 207 Introduction to Human Neuroanatomy The problem of CNS regeneration

Spinal cord damage is a mortal condition (10-15 per million per year UK) Damage caused by stroke is permanent Neurological conditions involving cell loss are irreversible (Alzheimers

disease, Parkinsons disease) Mortality associated with spinal injury has only recently fallen 2500 BC an ailment not to be treated WW1 only 10% survived a year- 1%

more than 20 years 1960s 35% died 1983 7.87x normal mortality. 20 yr old can expect to live 30 years What factors influence whether a cell regenerates? External factors

NGF, BDNF Internal messengers kinases, proteases Environmental factors macrophages, hydrogels, glia receptors Internal genetic state

Substrate factors laminin, In-1 How can we tackle this problem? Change the environment

peripheral nerve graft ensheathing glia hydrogels fetal tissue proteases

blood substitutes BUT only a few fibres regenerate Provide Growth Factors? NGF only works on peripheral nerves BDNF? Genetically engineered cells?

Improve the substrate? laminin osmotic pumps artificial substrates Change the cell? Engineer more receptors Up-regulate internal messengers use different cells?

Fetal cells Stem cells Will mammalian spinal cords make the right connections even if we do get regeneration? No retinotopy in lizard regeneration? No retinotopy in regeneration along sciatic nerve?

Retinal transplants do not form a retinotopic projection? What can and cant regenerate?

Adult fish can regenerate everything! Larval amphibia too, adults slowly? Reptiles slowly and without specificity Mammalian PNS Mammalian olfactory tract Mammalian nerves can only sprout abortively

Are fish different? Why study preamniotes? Can differences give clues? Can we do novel experiments? How do their spinal

cords regenerate? Why study Lower Vertebrates? They regenerate quickly and are simple to maintain. Embryos are readily available They have many tracts in common with mammals They show many of the growth factors, ECM

components and even collapsins found in mammals Two approaches have been used 1. Assuming similar processes act in all species use them as a model system for testing the ability of

fibres to regenerate under experimental conditions 2. To deliberately look for clues in the differences between the regenerating and non-regenerating

species How different are they? They grow throughout life Level of myelin inhibitory factor low in adult animals? (or localised?) Glial response to injury different? Extracellular environment more condusive to regeneration?

Are their neurons different? Added throughout life Less need for growth factors? Less cell death after axotomy Do NOT all regenerate

Inhibiting factors ARE present in fish CNS? Regenerating fibres prefer the PNS? (Bentley and Zottoli 1993) Ventral root Fish optic nerve not permissive for adult nerves

(Sivron et al 1994) cut site Is the balance different ? L1 NGF BNTF

ECM MIF-1 cell death MAG What does a regenerated spinal cord look like?

Which fibres regenerate? Do they grow back to their normal tracts? Do they find the correct targets? Is this process an extension of growth?

Can Spinal Axons tell Right from Left? R L R ?

RL Cut L R

? ? L The problem of order

Spinal cord in culture Direct cell heaters Work well in closed systems Ideal for imaging as they allow DIC and Fluorescence concurrently Small amounts of media Allow long term culture

Only heat cells Must use objective heater with immersion optics Closed stage system Thermocouple

inlet drain Contacts for glass heaters Phase and Dark Field Artificial Substrates

Saima Majeed

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