Altering the muscle environment to influence stem cell behaviour
This PhD studentship will investigate new ways of improving the efficiency of stem cell transplantation in degenerating muscle. Professor Jennifer Morgan and her colleagues at University College London have already discovered that treating an area of damaged muscle with radiation (like a very powerful x-ray) can increase the ability of transplanted stem cells to repair damaged muscle. As radiation can be harmful this project will investigate other less harmful ways of reproducing this beneficial effect.
This project is funded by the Duchenne Forum – a collaboration established to accelerate progress in the search for treatments and eventually cures.
What are the researchers aiming to do?
Satellite cells, the stem cells of skeletal muscle, are responsible for the repair and replacement of muscle fibres that are lost as a result of injury or wasting. Satellite cells are located on muscle fibres, in a niche between the cell membrane and the connective tissue surrounding the fibre. They are normally in a dormant state, but are awakened into activity by muscle damage. Chemical signals released by the muscle fibre and the connective tissue activate satellite cells and “instruct” them to multiply and migrate to where they are needed.
Researchers believe that satellite cell transplant (injecting healthy satellite cells into an individual) may one day offer a potential mechanism to treat neuromuscular conditions including Duchenne muscular dystrophy. Professor Morgan and her colleagues are researching ways to maximise the efficiency of stem cell transplantation in a mouse model of Duchenne muscular dystrophy. Using this mouse model, the researchers have already discovered that treating a specific area of the muscle with radiation (like a very powerful x-ray) before satellite cells are injected can improve the ability of the cells to repair the damaged muscle. However, the levels of radiation required are not safe for people with Duchenne muscular dystrophy. Professor Morgan and her PhD student will investigate how radiation improves the efficiency of stem cell transplants. This knowledge will help them identify new drugs or other factors that have the same effects as radiation, but without the harmful side effects. These molecules could then be used to improve the efficiency of stem cell transplants in the future,
Speaking about being awarded the grant, Professor Morgan said:
I am delighted to have been awarded this funding to appoint a PhD student. The work that they will perform during the course of their PhD will give us a detailed understanding of how to promote stem cells to efficiently repair and regenerate dystrophin-deficient muscles.
How will the outcomes of the research benefit patients?
This research will further our understanding of how stem cells can be used to repair and replace the wasting muscle cells in people with Duchenne muscular dystrophy. It will also help to explore the full potential of this approach as a treatment. By identifying factors or drugs that can increase the amount of muscle formed after satellite cells are transplanted, researchers may be able to increase the efficiency of this approach so it can be taken forward for testing in a clinical trial.
Year 1 progress:
We have found that there are significantly more dying cells within muscles that have been given a dose of radiation that has been shown to enhance the repopulation of the muscle by transplanted satellite cells. We have evidence that most of these dying cells are not satellite cells.
We have transplanted different types of muscle cells derived from irradiated muscles, mixed with satellite cells from normal muscles, into non-irradiated mdx mouse muscles, to see which one of these irradiated cells helps the satellite cells grow within muscle. These experiments are currently being analysed; preliminary results suggest that irradiated fibres are not the cause of the radiation-mediated effect.
Year 2 progress:
We are investigating ways to maximise the efficiency of stem cell transplantation in a mouse model of Duchenne muscular dystrophy. More specifically, we are studying how irradiation of the dystrophic mouse muscle before transplantation enhances the amount of muscle formed by the transplanted stem cells.
This year we have demonstrated that radiation improves stem cell transplants in dystrophic muscle but not in non-dystrophic muscle. We have shown that stem cells work best when transplanted into dystrophic muscles in which dying cells are present. We have transplanted different types of muscle cells extracted from irradiated muscles, mixed with stem cells from normal muscles, into non-irradiated dystrophic muscles, to see which one of these irradiated cell types helps the stem cells engraft into the muscle. The final results from these co-transplant experiments are currently being analysed.
We have also prepared samples to undergo next-generation sequencing, a high throughput technique that will allow us to see any changes in geneactivity throughout the whole genome, across the whole muscle, under different conditions. This will tell us what genetic pathways are changing significantly in response to radiation and guide further research.
Our future work for the coming year will be:
- To determine whether successful stem cell transplantation correlates with the number of dying cells present within the transplanted muscle.
- To complete the analysis of our co-transplant experiments, to determine which cells extracted from irradiated muscle can improve the function of muscle stem cells.
- To perform next generation sequencing, to allow us to see changes in gene expression in irradiated compared to non-irradiated muscles. This means we can find genes or groups of genes that could be important targets for therapeutic intervention that might promote more efficient stem cell transplantation.
Project leader: Professor Jennifer Morgan
Location: Institute of Child Health, University College London
Conditions: Duchenne muscular dystrophy
Duration: Four years, starting 2014
Total project cost: £111,225
Official title: The effect of modulating the dystrophic skeletal muscle environment on donor stem cell engraftment