Stem cells constitute a potentially important source of cells to repopulate and ameliorate disease states that afflict the elderly, such as Parkinson's, stroke, epilepsy and myopathy. This proposal is focused on increasing our understanding of one type of stem/pluripotent cell which is derived from adult bone marrow. We plan to extend our previous observations that bone marrow-derived cells from adult mice are capable of generating neuron-like cells in the brains of adult mice. Eight weeks following transplantation of green fluorescent protein (GFP) labeled adult bone marrow, the central nervous system of recipient mice was found to contain GPF-transplanted cells expressing several proteins specific to neuronal cells. This proposal aims to elucidate the factors and mechanisms responsible for this plasticity. Further, the environmental variables capable of enhancing this effect will be identified. The morphological and physiological properties of these bone marrow derived neurons will be assessed in a physiologically relevant context, specifically the murine hippocampus and neocortex in which repopulation of functional neurons would have therapeutic implications. The use of several transgenic murine lines with neural-specific promoters driving reporter genes such as GFP will be employed which should greatly increase the frequency of studying cells with neuronal properties. To evaluate the potential for adult bone marrow to serve as a viable source of cells and repopulate the brain, the following five points will be addressed.
In Specific Aim (1) and (2) the factors, such as injury, responsible for the homing of bone narrow derived stem cells to muscle and to the CNS and the differentiation signals which allow these cells to become muscle and brain will be ascertained. In addition, whether adult stem cells in bone marrow can transdifferentiate directly into muscle and brain or whether they must first acquire this potential by first reconstituting the blood will be assessed.
In Specific aim (3), the effect of age of donor cells and of recipient mice on the incorporation of transplanted cells into the host muscle and brain will be assessed.
In Specific Aim (4), whether a single bone marrow-derived stem cell can clonally give rise to muscle, brain and blood will be determined at the single cell level using retroviral marking.
In Specific Aim (5), once the frequency of cell fate changes and appropriate morphologies detected is increased, functional assays will be carried out by analyzing contraction in muscle and by using electrophysiological methods in neuronal cells. These studies will allow a rigorous assessment of the potential of using adult bone marrow cells to regenerate brain and brawn in a therapeutic setting in which the donor and the recipient are the same and issues of access, ethics, and immunogenicity are overcome. The results may contribute to novel therapeutic strategies for treating frequent diseases of the brain and muscle that afflict aging adults.
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