Development of retinal transplantation as an animal model to test stem cell therapies for myelin diseases

Stem cells can be used by scientists to form many of the different cell types that make up the human body. They offer exciting new possibilities for treating diseases of the human brain such as multiple sclerosis. By using human stem cells to grow new nerve cells in a dish, and then transplanting them into the brains of patients, we hope to repair the damage caused by the disease. The difficulty is that we have to be completely sure that these cells will not behave in a way that might make the brain damage worse, for example by growing uncontrollably and forming a tumour. Scientists believe that cells that have been completely turned into nerve cells will not cause these problems and will be effective at damage repair, but they do need to prove this each time they want to use a set of cells for treating groups of patients. At the moment this would be done by transplanting the cells into the brains of rats or mice. However, as the brain is a very complicated structure, it is extremely difficult to be completely certain that all the cells are behaving normally. This project proposes a new way of testing cells by placing them in the back of the eye of rats. The nerve fibres at the back of the eye are very similar to those damaged in diseases such as multiple sclerosis. Here, unlike the brain, the transplanted cells can be easily seen and tested. If successful, the project will both reduce the number of animals needed for testing stem cell treatments and also speed up the use of these treatments for brain diseases for which there is presently no cure

Cell transplantation represents an important application for stem cell medicine, with potential therapeutic benefit deriving from a combination of cell replacement and stimulation of endogenous repair. Diseases of the central nervous system, with their enormous societal and social costs, represent important targets for such therapies. Of these, the diseases of myelin provide appropriate initial targets; the oligodendrocytes lost or damaged in these diseases represent a functionally homogeneous population which extensive animal studies have established can be replaced by transplanted cells and whose replacement does not require complex targeting strategies. Key problems with transplantation of human ES or iPS cell-derived oligodendrocytes are, however, comparison of efficacy and confirmation of safety. Transplantation into animal models is clearly required, but assessment of behaviour within the complex 3-dimentional environment of the brain is a significant problem and represents a major roadblock in the path to clinical delivery of stem cell medicines. Here, therefore, we will take advantage of the unique architecture of the retina to develop a new preclinical animal model that overcomes these problems. The axons of retinal ganglion cells run in a flat sheet over the surface of the retina prior to their exit into the optic nerve. In the nerve, these axons are fully myelinated but they remain unmyelinated in their retinal portion. This reflects a lack of cells with myelinating capacity rather than any intrinsic properties of the axons, as we and others have shown that transplantation of precursor cells for oligodendrocytes into this retinal nerve fibre layer results in myelination. As the retina can easily be accessed and visualised through the eye in living animals, and then removed and flat mounted for histological analysis that enables quantification of myelination simply by measuring the area of myelinated axons, this has the potential to provide a simple and accurate model of efficacy and safety of myelinogenic cell populations prior to clinical use.