5 research outputs found
Multipotential Neural Precursors Transplanted into the Metachromatic Leukodystrophy Brain Fail to Generate Oligodendrocytes but Contribute to Limit Brain Dysfunction
Neural stem cells appear to be best suited for regenerative
therapy in neurological diseases. However, the effects of high
levels of potentially toxic substances such as sulfatides \u2013
which accumulate in metachromatic leukodystrophy
(MLD) \u2013 on this regenerative ability are still largely unclear.
To start addressing this question, in vitro and in vivo experiments
were used to examine the behavior of multipotential
neural precursors exposed to abnormally high levels of sulfatides.
Following transplantation of dissociated neurospheres
into the brain of presymptomatic MLD pups, the majority
of donor-derived cells were distributed in a caudal to
rostral direction, with higher numbers in the cortex. Most if
not all of the donor cells acquired an astroglial phenotype.
We found no evidence of oligodendrocyte or neuronal commitment
of transplanted cells in long-term-treated MLD
mice (e.g. up to 1.5 years of age). This was in line with our in
vitro findings of sulfatides blocking oligodendrocyte formation
after induction of differentiation in sulfatide-treated epidermal growth factor/fibroblast growth factor responsive
neurospheres. Transplanted MLD mice showed an improved
arylsulfatase A (ARSA) activity and a significant amelioration
of sulfatide metabolism, neurodegeneration and
motor-learning/memory deficits. Furthermore, transplanted
cells were shown to act as a source of ARSA enzyme that accumulated
in endogenous brain cells, indicating the occurrence
of enzyme cross-correction between transplanted and
host cells. These results provide a first insight into the effect
of sulfatides on the stemness properties of neural stem cells
and on the effects of the MLD environment on the in vivo
expectations of using neural stem cells in cell ther apy