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--which accumulate in metachromatic leukodystrophy (MLD)--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 therapy.
Givogri
M I
MI
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL , USA. mgivogri@uic.edu
Bottai
D
D
Zhu
H L
HL
Fasano
S
S
Lamorte
G
G
Brambilla
R
R
Vescovi
A
A
Wrabetz
L
L
Bongarzone
E
E
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000503:physiopathology; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013433:Sulfoglycosphingolipids / Q000378:metabolism
D013433:Sulfoglycosphingolipids; D049452:Green Fluorescent Proteins; D002553:Cerebroside-Sulfatase