Amyotrophic lateral sclerosis (ALS) is a fatal adult onset neurological disorder that characteristically involve the degeneration of motor neurons. No effective treatment exists to substantially retard the progression of this disease, or to reverse the devastating and fatal disability. The use of stem cells in general and astroglial in particular, appears to represent a new approach to the treatment of neurodegenerative disease: rather than directly combating a pathological process, stem cell-based strategies could reinvoke developmental processes to insert new cells seamlessly into the degenerated environment. Recent studies document the potential of certain stem cells in promoting neuroprotection/recovery in a variety of nervous system injuries. The overall goal of this proposal will be to study the potential of murine astroglial stem cell transplantation as a therapeutic modality for the treatment of animal models ALS. In ALS patients and in animal models, defects in astroglial glutamate transporter GLT-1/EAAT2 lead to excitotoxic neural degeneration. Preliminary studies document that replacement of glutamate transport can effectively and dramatically slow down the disease; while use of selected trophic factors can enhance motor axon growth and also protect motor neurons. Glial-restricted progenitor cells appear to be able to engraft into spinal cord explants (in vitro), express the potentially neuroprotective astroglial GLT-1/EAAT2 glutamate transporter, and potently protect against glutamate-mediated neuronal death. The overall goal of this proposal will be to: 1) Characterize the normal regulation of glutamate transporter subtypes in glial progenitor cells in vitro and after engraftment; 2) Establish the neuroprotection by glial progenitor stem cells using in vitro models. To critically evaluate the role of glutamate transporter versus other properties of GRP (e.g. trophic factor release) we will perform comparisons with GRPs prepared from transporter null mice (GLT-1, GLAST, GLT-1/GLAST); 3) Determine if glial progenitor cells can protect against chronic neuronal injury by examining stem cell differentiation and neuroprotection in vivo in a transgenic animal model of ALS - G93A SOD 1 mutant mice and rats. Over all, these studies will provide data on the utility of astroglial stem cells to alter neurodegeneration in acute and chronic injury models relevant to ALS and hopefully provide important critical pre-clinical information.
