MND Association-funded researcher, Prof Linda Greensmith, based at University College London, together with her collaborator Dr Ivo Lieberam from Kings College London, have introduced stem cell-derived motor neurones into mice. Published in the prestigious journal Science on 4 April 2014, her research has also demonstrated that muscle function can be controlled by light.
MND Researchers use a range of models to further our understanding of MND. These can be animal models, such as mice and zebrafish, or cellular models, such as induced pluripotent stem (iPS) cell-derived motor neurones (as described by Association-funded researcher, Dr Ruxandra Muthiac, during the Spring Conference in Newport on Sunday 6 April).
These models enable us to find out more about the causes of MND by studying how changes in the genes (our genetic makeup) give rise to MND. Not only this, models of MND are the essential ‘first step’ in screening potential new MND drugs before they go on to human trials.
Prof Greensmith and her team of researchers used an early stage mouse model of MND. By using this model she was able to investigate if embryonic stem cell-derived motor neurones could be successfully transplanted into mice and whether muscle function could be controlled by light.
Creating and transplanting
There are many different types of stem cells including adult, embryonic and iPS cells. These cells are used in very different ways and you can find out more about them, and their uses in MND research, in our stem cells and MND information sheet.
Dr Lieberam used embryonic stem cells from ‘healthy’ mice and engineered them into motor neurones, using a cocktail of chemicals. He then modified them further in order for them to express a light sensitive compound, as well as a long-term motor neurone survival factor.
This survival factor allowed the cells to survive long enough for them to be transplanted into the mice, whereas the light sensitive compound enabled the researchers to stimulate the cells using a specific wavelength of light.
Once the motor neurones had been successfully modified, Prof Greensmith transplanted them into the sciatic nerve whilst the mice were anaesthetised. The sciatic nerve is the longest nerve in the body and spans from the lower back to the lower leg.
After the initial transplant, Prof Greensmith’s team established that the motor neurones were able to:
- survive for over 35 days
- grow towards the muscles in the legs and form attachments
- grow and develop into mature motor neurones.
These three factors, in combination, offer hope for the transplantation of stem cell-derived motor neurones in MND.
Once the researchers had successfully transplanted the cells, the next step was for them to find out if they could be stimulated by light and activate the muscles to contract.
Normally, when we move our hand, our brain sends a message via the upper motor neurones to the spinal cord. From here, the lower motor neurones continue to send the message to the muscles in our hand, which then contract and cause movement.
In order to activate the transplanted motor neurones in the mice, the researchers needed to ‘substitute’ the upper motor neurones with another stimulus eg light.
The mice were anaesthetised and a specific type of blue light was shone onto the motor neurones in the sciatic nerve. This specific type of light reacted with the light sensitive compound within the motor neurones and caused them to initiate nerve impulses. As the motor neurones had already formed connections with the muscles, the nerve impulses resulted in controlled muscle contractions.
What this means for MND research?
This research has shown that it is possible to restore muscle function by transplanting stem cell derived motor neurones and then stimulating them with light. However, further research is needed as there are still a number of challenges to overcome.
For example, this research is a ‘proof-of-principle’ study, meaning the researchers have shown for the first time that this strategy works, but further work needed. The research would now need to be repeated by other researchers before it can be translated to people living with MND.
Another challenge to overcome would be the fact that the motor neurones were only stimulated directly by exposing the nerve in the leg and shining the blue light over the nerve. Obviously, this would not be feasible in people living with MND and Prof Greensmith has highlighted that an implantable light device that would allow long-term stimulation of the transplanted cells will need to be developed in order for the motor neurones to be stimulated inside the body in un-anesthetised mice.
Prof Greensmith comments on her research, what it means and future steps:
“This proof-of-principle study, undertaken in collaboration with Dr Ivo Lieberam confirms that it is possible to transplant stem cell-derived motor neurons, which have been modified to respond to blue light. These transplanted cells can then be stimulated by light to make the muscles they form connections with contract.
“This approach overcomes many of the challenges faced by most studies using stem cells to restore muscle function in MND, in which the stem cells are transplanted into the spinal cord, where they must form appropriate connections with the inputs from the brain if they are to be stimulated. In our approach, we can directly and specifically control the transplanted cells.
“However, there are several hurdles we must now overcome if we are to translate these findings into an strategy that can used in people living with MND. Our initial aim is to try and restore function to the muscles that are responsible for breathing, as this is a relatively simple type of muscle function. The next step is to develop an optical stimulator that can be implanted into the body to stimulate the transplanted cells for long periods of time. Once we have confirmed that the transplanted cells can be activated and survive for long periods, we will begin to develop this technique to restore function to the respiratory muscles.
“Therefore, although we are very excited by our findings, and believe that they represent the first step in the development of an optical pacemaker to restore muscle function, we are keen to emphasise that we are at the very beginning of the project, and that any patient-based studies are likely to be several years away.”