Cell-based therapy for SCI

The morning’s session on the final day of SfN2010 included a number of posters on cell transplantation strategies for SCI.

Schwann cells derived from skin precursors (SKP-SCs) have been reported to improve outcomes despite less than 20% cell survival in the damaged cord. Sparling sought to improve SKP-SC with Neuregulin and other co-treatments expected to enhance graft survival.

With the various co-treatments the group found cell survival and cell bridges extending above and below the lesion cavity but no significant increase in graft volume. Despite this, of all the different treatment groups SKP-SCs + Neuregulin appeared to have the least “variability” and largest average graft volume. In other words, there might be a trend towards increased cell survival. In terms of mechanism, evidence of transplanted SKP-SCs myelinating axons was presented as was increased endogenous Schwann cells (ie those coming into the cord from the periphery where they normally reside).

P. Assinck (from the same lab) examined the fate and outcomes following SKP-SC transplant into the chronic injury. They took rats and transplanted one million cells into the lesion site 8 weeks after thoracic contusion injury. SKP-SCs prevented the decline of forelimb and hindlimb stride length (Catwalk) and elicited a trend towards higher BBB scores, which reached significance in week 17 and 19 after injury. SKP-SCs survived for 21 weeks post injury in all transplanted animals albeit to various degrees. As with acute transplantation, SKP-SCs appeared to facilitate the recruitment of endogenous Schwann cells in the injured cord, and it certainly looked like SKP-SCs modified the Glial scar (less astrocyte hypertrophy in areas containing the transplanted SKP-SCs).

SKP-SCs are suggested as a potentially useful (autologous) source of cells but one must assume we are really only going to isolate from the patient and expand in culture after the injury. As cell expansion will take some time the viability of these cells as a treatment is dependant on being effective in the sub-acute/chronic injury environment making the observation presented here all the more important.

Stephen Davies continued his work on the importance of knowing and controlling the growth conditions of developing astrocytes. Previous work had shown that astrocytes grown in different media end up with quite distinct properties. If you take precursor cells and drive growth using BMP the resultant astrocytes have some beneficial properties. By contrast, if they are grown in the presence of CNTF they can cause undesirable side effects such as pain. The work presented today centred once again on characterisation these two astrocyte populations but this time derived from human fetal cells. Human derived astrocytes generated via BMP induction promoted neuroproetction and recovery in a rat SCI models whilst those induced with CNTF failed to promote locomotor function, in line with that found using rodent tissue. Rodent tissue is not going to be used in humans so confirming human cells have the same properties is an important step towards translation.

There was also a little buzz around a poster from P Lu. Embryonic spinal cord neurons when transplanted into the spinal cord faciliate robust growth of long axons descending the cord into the graft. Less is known about how these cells react within the injured environment or whether they themselves send out axons and integrate functionally. To help answer this, Lu and colleagues used embryonic spinal cord cells from rats that have been infected with a virus that carries a green fluorescent protein (GFP) so they could visualise the fate of embryonic spinal cord cells after transplantation. They transplanted these cells into an injury and found they threw out axons over remarkably long distances and moreover they form synapses with host neurons, become myelinated, connect into the grey matter. What is significant is that these embryonic cells clearly find the so-called inhibitory mature nervous system permissive to regeneration and may be capable of forming functional relays connecting host circuits above and below the injury that were previously disconnected.

Maths & medicine go hand-in-hand

Developing treatments for SCI might be broken down into different phases. It begins with understanding what a SCI actually is – what happens after the immediate injury and changes that occur in the spinal cord during the following months – and from there identify which of the various changes or processes might be amenable to treatment interventions – in other words, identify a therapeutic target. This needs to be tested to establish the proof of principle that this target might be beneficial to outcome which might mean switching off a gene that makes a protein that you believe is one of the reasons neurons fail to regenerate after injury.

But there are so many things happening in the cord after injury and so many possible interacting processes, that identifying one single target is extremely difficult. This is why researchers appear to be working on lots of different concepts generating data. It is not that one group is right and all the others are barking up the wrong tree, it is that each concept may well have the potential to be helpful and the question really comes down to which one is most helpful or most central to repair.

In addition, spinal cord injury (SCI) really needs to be thought of as a syndrome with loss of mobility, sensation, loss of bladder/bowel and sexual function and pain amongst the most devastating. As a consequence we have had to develop many models to emulate these so that we can test the effectiveness of potential treatments.
Given the sheer complexity of SCI it is little wonder it has taken decades of basic research to get to the stage we are now. In the last 20 years in particular we have seen significant progress but few treatments have been successfully translated to the clinic for evaluation in humans. One major obstacle to translation is not being able to compare data from one lab or animal model or species because if we could we would be better placed to make judgements on the robustness of an experimental treatment and the “likelihood” it will work on the most important species we need to consider – humans.

Adam Ferguson is trying to address this problem. He is collecting data from many labs (with their different injury model, severities, species etc.) and looking for consistent patterns in that data – using sophisticated mathematical techniques – so that he can identify measurable outcomes that are most sensitive to the species used, most sensitive to the severity of the injury and those which are most sensitive to the changes over time after injury. It requires huge amounts of data and he has collected data from studies reaching back 9 years to achieve this. Experimental treatments that “shine” within these patterns are more likely to translate to humans.

Fish oil and spinal cord injury

We're always being told fish oil is good for us. Eat more oily fish. Well apparently there is accumulating evidence, according to S. J. Gladman, that fish oils, and in particular a class of fish oils known as Omega-3, has some remarkable therapeutic potential in a number of disorders of the nervous system, including trauma. Using a cell-based model to replicate the mechanical stretch axons experience around the injury site of a cord lesion, the group from London, who are developing this concept and hope to take it to clinical trial in the near future, have shown significant reduction in cell death after treatment with Omega-3. They went further and found that if, in this model, they used neuronal cells derived from mice that have naturally high levels of Omega-3 AND added Omega-3 cell death was totally abolished. Omega-3 appears to confer neuroprotective effects and will likely only be useful if given in the immediate aftermath of injury.

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Omega-3 polyunsaturated fatty acids have different chemical forms, for example docosahexaenoic acid (DHA) or alpha-linolenic acid (ALA). Jodie Hall presented a poster on the effects on dietary eicosapentaenoic acid (EPA) in rats with SCI. Surprisingly, when given an EPA-rich diet rats did less well in locomotors tests in contrast to when they received EPA by injection. Why this is is unclear and further work is ongoing to understand why the route of delivery is so important.

Elsewhere M. S. Joseph combined Omega-3 with curcumin (a curry spice) in the diet and found it enhanced learning of new tasks by circuits in the spinal cord after SCI. I suppose we should really be eating fish curry.

Society for Neuroscience: Day 1

Twenty-fours travel (door to door) and setting up our exhibitors booth left just time to relax a little before the marathon Society for Neuroscience Annual Meeting, San Diego began in earnest. In this day and age of heightened security and baggage scanning it was somewhat amazing that a suitcase containing a plastic and metal, anatomically-correct sized, model of a spinal cord got through without questions. Well actually, our over overweight suitcase, had been “physically inspected” a little leaflet inside revealed – so faith restored in the US Department of Homeland Security.

Speaking of security, we had been warned there was a demonstration against research on animals planned to coincide with the first day. If I hadn’t known about it I would have walked right by without noticing it which is different from scenes I’ve witness in the UK in the past. But it does inspire me to blog at a later date on the use of animals in research as it is an important issue.

The meeting proper kicked off today with the first afternoon of poster presentations. Spinal cord injury research was amongst those topics represented during this first session in a series of posters devoted to plasticity. Plasticity of the nervous system plays an important role in the way the nervous system adapts to experience and injury. The myriad of connections between neurons of the nervous system are not entirely fixed and can and do change in response to stimuli. Understanding plasticity and manipulating it may offer one of the most promising avenues of repair for many conditions including SCI.

So it was good to get an opportunity to visit Leanne Ramer’s poster that presented some work that may shed light on two serious consequences/complications of SCI, namely pain and autonomic dysreflexia. Pain needs no explanation, but autonomic dysreflexia (AD) probably does. The autonomic nervous system controls parts and functions of the body that we take for granted and we are largely not aware of, such as heart rate, bladder function blood pressure etc. When it goes wrong, as in (AD), the consequences can be serious. SCI not only affects movement and sensation but also the autonomic system but it was not clear how. SCI stimulates plasticity in autonomic nervous system leading to new (inappropriate) connections into parts of the nervous system that are involved in sensation. The upshot being signals being sent from organs such as the bladder start to stimulate the autonomic nervous system dealing with things like blood pressure; bladder becomes too full, blood pressure sky-rockets. Ramer showed that in addition to this the sensory parts change and become more active, exacerbating the problem.

Has it really been a year?

Spinal Research heads off to the 40th Annual Society for Neuroscience Meeting in San Diego (13-17 Nov).

 

Look out for posts on research emerging in the field of spinal cord injury (and maybe beyond). You can also find other blogs covering the meeting.

If you're attending the meeting this year come visit our booth in the nonprofit section (Booth #3824)