"Global" cell replacement is feasible via neural stem cell transplantation: Evidence from the dysmyelinated shiverer mouse brain

Many diseases of the central nervous system (CNS), particularly those of ge netic, metabolic, or infectious/inflammatory etiology, are characterized by "global" neural degeneration or dysfunction. Therapy might require widespr ead neural cell replacement, a challenge not regarded conventionally as ame nable to neural transplantation. Mouse mutants characterized by CNS-wide wh ite matter disease provide ideal models for testing the hypothesis that neu ral stem cell transplantation might compensate for defective neural cell ty pes in neuropathologies requiring cell replacement throughout the brain. Th e oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally" dysfunctional because they lack myelin basic protein (MBP) essential for e ffective myelination, Therapy, therefore, requires widespread replacement w ith MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth-using a simple intracerebroventricular implantation technique-resu lted in widespread engraftment throughout the shi brain with repletion of M BP, Accordingly, of the many donor cells that differentiated into oligodend roglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean = app roximate to 40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore , "global" neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.