A promising approach to alleviating the symptoms of Parkinson's disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of dopaminergic neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines.
While transplantation has been promising, it has had limited success, in part due to the ability of the transplanted neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function.
We have had ongoing efforts in our lab to determine the key guidance molecules that are required for proper targeting of normal fetal dopaminergic neurons during development and have identified necessary cues. We now plan to extend these studies to determine how these critical guidance cues affect human stem cell derived dopaminergic neurons, the cells that will be used in transplantation. In addition, we will examine how these guidance cues affect both normal and stem cell derived neurons under conditions that are similar to the transplanted brain, specifically when the brain is inflamed. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.
The researchers looked for factors that help guide dopamine neuron projections to their targets areas in the striatum. Identification of these factors could be used to promote growth from grafted dopamine cells and to improve their ability to make connections with the host brain and improve outcomes for cell transplantation therapy. They identified a number of factors and have found several of these to be capable of directly axon outgrowth from cultures of rat midbrain tissue (although not from mouse midbrain). Dopamine neurons derived from embryonic stem cells were also responsive to guidance cues. Much work remains, though, to perform a more exhaustive and quantitative study.