Central nervous system (CNS) disorders such as those that affect the brain and eye are particularly debilitating because repair is hampered by the fact that neurons don’t divide to replace damaged areas and adult neural stem cells that can divide and potentially replace neurons don’t do so in the adult (for reasons we don’t understand). Therefore, it is intriguing to think that disorders such as stroke and macular degeneration of the eye may benefit from stem cell therapy. Treatment with stem cells derived from human embryonic stem cells (hESCs) requires pre-formation of a particular cell type, since transplantation of hESCs themselves leads to tumor formation. However, current methods for making CNS neurons are inadequate since the neurons are usually immature and unable to connect with the other neurons in the damaged area. Interestingly, treatment of animal models of CNS disorders with stem cells has shown some limited benefits without generation of mature neurons, possibly due to factors that the cells produce. However, transplantation of brain- or eye-specific cells derived from hESCs may lead to greater functional recovery (e.g. treatment of the damaged brain with a brain-specific neuron able to make functional connections with the host tissue). Certain regions of the brain (cortical) and eye (retinal) arise from the same area during development and share expression of a variety of markers, including regulatory proteins called transcription factors. Thus, it should be possible to make brain and eye cells from hESCs using similar conditions.
Our goal is to use transcription factors to preferentially form brain and eye cells from hESCs. In one set of experiments, we will analyze transcription factors made by the hESCs in response to exposure to different conditions. In our second set of experiments, we will put transcription factors into hESCs during differentiation to test whether a particular transcription factor can direct formation of brain or eye neurons. This approach was recently shown to improve generation of the particular type of neurons damaged in Parkinson’s disease from mouse ESCs. We hope to use the cells we make for transplantation and also for drug testing, since there is currently no large-scale source of human versions of brain and eye neurons for these purposes.
Statement of Benefit to California:
The goal of this project is to make brain- and eye-specific cells from hESCs that can be used for transplantation for disorders that affect specific brain regions (such as stroke) or the eye (retinal disorders such as macular degeneration). We also expect that the cells derived in this project could be used as a source of human brain or eye neurons for drug testing. Currently, there is no large-scale supply of such neurons. As such, if the goals of this project are realized, the benefits to the State of California and its citizens would include a greater range of therapeutic options for central nervous system disorders as well as an important source of cells for pharmaceutical and biotechnology companies.