This proposals aims are to identify the molecular attributes that facilitate engraftment and migration in the CNS of adult stem cells from bone marrow, referred to as Mesenchymal Stem Cells (MSCs), and evaluate the efficacy and potency of sub populations enriched for these factors as cellular vectors for treating neurodegeneration in an animal model of lysosomal storage disease. Specifically, GFP-expressing MSCs engrafted in the CNS of neonatal and adult mice will be recovered by fluorescence-activated cell sorting and their transcriptome catalogued via serial analysis of gene expression. The latter will be compared to the initial injected population to identify molecules enriched in the engrafted sub population. Particular emphasis will be placed on evaluating the expression levels of axon guidance and neural cell adhesion molecules previously shown to be expressed by MSCs that are known to mediate neuronal cell migration. The distribution of factors enriched in engrafted cells will be delineated in MSC populations and correlated with the expression levels of other important neuro-regulatory factors they express, including various neurotrophins and neurite-inducing molecules. Subsequently, the overall engraftment potential in the CNS of MSC sub populations demarcated based on their differential expression of these factors will be compared to that of unfractionated cells in normal mice using a quantitative real-time PCR assay. Those populations that exhibit the best engraftment will then be transplanted into the CNS of mice afflicted with mucopolysaccaridohsis Type VII and their efficacy and potency in retarding or reversing the extent of storgage disease will be evaluated using biochemical and histochemical techniques. By identifying the unique attributes that facilitate engraftment of adult stem cells in the CNS, these studies will provide a means to isolate more potent celluar vectors for treating CNS neurodegeneration associated with various forms of storage disease and as such have a direct affect on human health and disease.