Integration and differentiation of neural stem cells after transplantation into the dysmyelinated central nervous system of adult mice

Mutant mice deficient in the myelin-associated glycoprotein (MAG) and the nonreceptor-type tyrosine kinase Fyn are characterized by a severely hypomyelinated central nervous system (CNS) and morphologically abnormal myelin sheaths. Despite this pronounced phenotype, MAG/Fyn-deficient mice have a normal longevity. In the present study, we took advantage of the normal life expectancy of this myelin mutant and grafted neural stem cells (NSCs) into the CNS of MAG/Fyn-deficient mice to study in short- and long-term experiments the fate of NSCs in adult dysmyelinated brains. Neural stem cells were isolated from spinal cords of transgenic mouse embryos ubiquitously expressing enhanced green fluorescent protein. Cells were expanded in vitro in the presence of mitogens for up to 5 weeks before they were grafted into the lateral ventricles or injected into white matter tracts. Analysis of mutant brains 3-15 weeks after intracerebroventricular transplantation of NSCs revealed only limited integration of donor cells into the host brains. However, injection of NSCs directly into white matter tracts resulted in widespread distribution of donor cells within the host tissue. Donor cells survived for at least 15 weeks in adult host brains. The majority of grafted cells populated white matter tracts and differentiated into oligodendrocytes that myelinated host axons. Results suggest that intraparenchymal transplantation of NSCs might be a strategy to reconstruct myelin in dysmyelinated adult brains.