Early step toward spinal cord repair

Friday August 13 2010

Scientists have “encouraged substantial re-growth in nerves controlling voluntary movement after spinal cord injury,” reported BBC News.

This news story is based on experimental animal research that found that, by deleting a gene called Pten in mice, the growth of spinal cord nerve cells could be encouraged following spinal cord injury.

This is exciting but early research and the researchers have not yet investigated whether the nerve cell regrowth observed is sufficient to restore function following spinal cord injury in mice. As the BBC points out, the genetic engineering techniques used in this study are highly experimental and may not be feasible treatment options for humans. Much more research is needed to see how well this experiment could relate to humans and whether it could be translated into treatment options for people with a spinal cord injury.

Where did the story come from?

The study was by researchers from Harvard Medical School and funded by organisations including: Wings for Life, the Dr Miriam and Sheldon G Adelson Medical Research Foundation, the Craig H Neilson Foundation, the US National Institute of Neurological Disorders and Stroke, and the International Spinal Research Trust. It was published in the peer-reviewed journal, Nature Neuroscience. This research was reported very accurately by the BBC.

What kind of research was this?

This was an animal study that investigated whether it was possible to promote regrowth of neurones (nerve cells) in the spinal cord of adult mice. Neurones lose the ability to regrow in adults, and attempts to stimulate spinal cord neuron regrowth in adult mammals have only had limited success to date.

The researchers say that they had previously found that in damaged optic nerves the activity of a gene called mTOR, which contains the instructions for making the mTOR protein, determines whether the neurones will regrow. If the mTOR gene is more active and produces more mTOR protein, it encourages enhanced regrowth. The researchers wanted to see if their findings in the optic nerve were also relevant to spinal cord neurone regrowth.

As this is an animal study that involved genetic engineering, its application to humans with spinal cord injury is limited. However, in the long term, greater understanding of the biological mechanisms that normally prevent adult spinal cord neurons from regenerating may offer leads to treating huamn spinal injuries.

What did the research involve?

To look at the response of neurones to spinal cord injury, the researchers used mice and severed the neurones on one side of the top of the mouse’s spinal cord, just by the base of the brain. They then injected a dye that would travel from the brain down through the spinal cord and therefore only show up in intact neurones. The researchers could then look to see whether there was any “compensatory sprouting” or growth of the healthy neurones – a process where the healthy neurones on the uninjured side grow into the injured side. They carried out this experiment in mice of different ages to see how age affected the ability of the neurons to regrow.

They also looked to see how much mTOR protein was present in these mice of different ages, to see if the mTOR-producing gene could account for any differences in the ability of the neurons to show compensatory sprouting.

A protein called “Pten” is known to reduce activity of mTOR, so the researchers wanted to test what would happen if mice with spinal injuries did not produce Pten. To do this they used a genetic engineering technique that allowed them to delete the Pten gene in mice after birth. They looked at whether adult mice lacking the Pten gene with injured spinal cords would show neuronal sprouting similar to younger mice.

In later experiments, the researchers took a new set of mice and again caused spinal cord injury on one side of the spinal cord, but this time they did it lower down than in the first set of experiments. They then looked at growth over two weeks by injecting dye into the injured neurones. They looked at how the injury affected mTOR activity in the neurones, and whether prior deletion of the Pten gene affected this.

Finally, they looked at what happened in mice lacking Pten and normal control mice when they caused the injury either by making a cut to the spinal cord or by simulating a crush injury of the spine.

What were the basic results?

When the one-week-old mice had the top of the spinal cord cut on one side, the researchers found that intact neurones from the other side started showing signs of compensatory sprouting and growing into the injured side. In older mice this did not occur. They found that as mice aged, their neurons produced less mTOR protein, suggesting that this could be related to the differences in neuronal sprouting seen.

The researchers found that when they deleted Pten the activity of mTOR was increased in adult neurones. They found that if they deleted Pten in newborn mice and then caused neurone injury  when the mice were adults, then there was extensive compensatory growth of the healthy neurones.

The researchers next looked at the effects of cutting lower down in the spinal cord rather than at the top of the spinal cord at the base of the brain. They found that with this injury the mTOR activity in these spinal cord neurones was lowered, but if they deleted the Pten gene then the decrease of mTOR activity that was caused by this injury was prevented. They found that in mice lacking Pten there was more regeneration, with neurones either growing through or around the area of spinal cord damage. This did not occur in normal, unmodified mice.

After a crush injury to the spinal cord, no neurones grew beyond the injury site in the control mice, but in the mice where Pten had been deleted the neurones grew into or around the damaged site by 12 weeks after the injury in all eight mice tested. They found that these results were similar in younger two-month-old mice and older five-month-old mice.

For neurones to be functional after damage, they need to form synapses – areas at their ends that pass on neurone impulse signals to the next neurone cell. The researchers found that the neurones that had grown in the Pten deletion mice had structures that looked like synapses at their ends and contained some proteins that are only found in synapses. However, they did not assess whether these synapses were functional, i.e. that they could pass messages to the neighbouring neurone.

How did the researchers interpret the results?

The researchers concluded that increasing  mTOR activity through the deletion of the Pten gene enables injured adult spinal cord neurones to “mount a robust regenerative response” that “has not been observed previously in the mammalian spinal cord”. They suggest that a strategy combining PTEN deletion, neutralising chemicals to promote growth at the site of injury and tissue grafts that promote neurone growth may lead to optimal neurone regeneration after spinal cord injury.

Conclusion

This was a well-conducted and useful animal study that demonstrated a link between the proteins mTOR and PTEN in regulating neurone growth after spinal cord injury. The researchers also demonstrated that deleting the Pten gene promoted neurone regrowth after spinal cord injury in adult mice.

The research did not look at whether the neurone regrowth was sufficient to allow the mice to recover function after spinal cord injury. This warrants further research. The researchers envisage that other strategies such as tissue grafts could be used alongside their technique to promote neurone regrowth.

As this study was conducted in mice, much more research is needed to assess whether the same effects could be safely produced in humans. The manipulation of genes may not be a feasible therapeutic approach for people with a spinal cord injury, but it is possible that drugs could be used to exert a similar effect. However, as it stands this study makes a important contribution to the understanding of how to promote neurone regeneration in adult mammals.

Analysis by Bazian
Edited by NHS Website