Stem cells have the potential to treat and possibly cure a variety of disorders, particularly those of the central nervous system (CNS). To develop successful clinical therapies, the fate of these cells after grafting must be monitored in a noninvasive manner. Currently, there is a need to develop in vivo means to track transplanted cells to determine their survival and migration patterns. By attaching a magnetic tag to stem cells, we propose to follow their biodistribution in vivo using MR imaging. We hypothesize that MR monitoring of the extent of cell migration, including the local distribution within the CNS, will allow for optimization of stem cell transplantation protocols, and that the same strategy may eventually be pursued in humans. Specifically, we will label bone marrow stem cells and neural stem cells obtained from mouse embryonic stem (ES) cell lines.
Our first aim i s to optimize the magnetic labeling procedure using superparamagnetic iron oxides that are coated with a transfection agent. Following magnetic tagging, we will then graft labeled cells into the CNS or inject cells systemically into the following four animal models of neurodegenerative disease: a) Long Evans shaker rat model of dysmyelination (aim 2); b) Twitcher mouse model of globoid cell leukodystrophy (aim 3); c) Sindbis virus rat model of lower motor neuron disease (aim 4); and d) mouse model of Parkinson's disease (aim 5). These models are believed to represent human CNS diseases that are likely candidates for future stem cell therapy. Using serial MR imaging of the same animal over time, unique information on the spatial temporal dynamics of cell migration can be obtained. Specifically, we aim to correlate the obtained MR contrast images with conventional histopathologic labeling and staining techniques for each differentiated cell type, to determine the extent of new myelination or dopaminergic neuron formation and the potential improvement in animal behavior. Upon the completion of our studies, we expect to demonstrate that MR tracking of magnetically labeled stem cells is a valid new technology for studying stem cell based therapies in the CNS, setting the stage for applying this technique in a clinical setting.
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