Transplantation of neural precursor cells into the dysmyelinated CNS of mutant mice deficient in the myelin-associated glycoprotein and Fyn tyrosine kinase

Abstract

We have studied in long-term experiments the fate of intraventricularly transplanted neural precursor cells in a dysmyelinated mouse brain. Precursor cells were isolated from striata or spinal cords of transgenic mouse embryos ubiquitously expressing enhanced green fluorescent protein (EGFP). Cells were expanded in vitro in the presence of mitogens for up to 14 weeks, and injected into the lateral ventricle of young postnatal mouse mutants deficient in the myelin-associated glycoprotein (MAG) and the nonreceptor-type tyrosine kinase Fyn. The CNS of these mutants is severely hypomyelinated and most myelin sheaths display ultrastructural abnormalities. Despite this phenotype, MAG/Fyn-deficient mice have a normal longevity. Analysis of mutant brains 1 to 6 months after transplantation revealed widespread distribution of EGFP-positive cells in the recipient tissue. Grafted cells preferentially populated white matter tracts and differentiated into a variety of morphologically distinct cell types. A significant fraction of donor cells was identified as oligodendrocytes. Electron microscopic analysis revealed the presence of numerous donor-derived, ultrastructurally intact, myelin sheaths around host axons. EGFP-positive oligodendrocytes and myelin survived for up to 6 months after transplantation, the latest time point investigated. Remarkably, the number of donor-derived oligodendrocytes increased significantly with increasing time intervals after transplantation, resulting in widespread myelination of 6-month-old host brains. These long-term experiments thus demonstrate that extensive myelination of a dysmyelinated brain can be achieved after a single injection of neural precursor cells.