EGF responsive multipotential neural stem cells harvested from the brains of mice and other species can be transplanted into various areas of the CNS where they differentiate into oligodendrocytes, astrocytes, and neurons, and contribute to normal structures, including myelin. Stem cell transplantation is useful as an experimental model of myelination and, potentially, as a therapeutic modality in demyelinating diseases such as Multiple Sclerosis (MS). The importance of graft derived oligodendrocytes, the myelin forming cells, in remyelination of host CNS is unambiguous. However, astrocytes also arise from engrafted stem cells. During embryogenesis, astrocytes and their precursors play a central role in the establishment of the cellular architecture of the brain and spinal cord (CNS histogenesis). In the mature CNS, astrocytes are essential in the maintenance of neural tissue homeostasis and response of the brain and spinal cord to injury and disease. The impact of astrocytes on the process of myelination is uncertain and has been neglected in most studies because they have been difficult to distinguish from host astrocytes. We propose a series of transplantation experiments in which we examine the influence of astrocytes of re-myelination in the CNS and explore the mechanism(s) mediating these effects. In the last Aim, we examine whether embryonic stem cells (ES cells) transplanted into the CNS are capable of integration, differentiation into astrocytes and oligodendrocytes, and formation of myelin. These studies probe the theoretical questions of what role astrocytes play in myelination, the mechanisms of these effects, and address the practical concern of how to optimize stem cell transplants. This research program complements and significantly extends the candidate's previous training consisting of a Veterinary degree, a Ph.D. in molecular biology, and residency training in Veterinary Anatomic Pathology. The program will be undertaken at the School of Veterinary Medicine at the University of Wisconsin- Madison under the mentorship of Dr. Albee Messing, who has expertise in mouse models of CNS degeneration and development, focusing on the role of glial cell types in these processes, and using both transgenic and stem cell technologies. The training program will prepare the candidate as a viable independent biomedical researcher specialized in developmental neurobiology and pathology.
