Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats.
BACKGROUND
Experimental therapeutics for degenerative and traumatic diseases of the nervous system have been recently enriched with the addition of neural stem cells (NSCs) as alternatives to fetal tissues for cell replacement. Neurodegenerative diseases present the additional problem that cell death signals may interfere with the viability of grafted cells. The adult spinal cord raises further challenges for NSC differentiation because of lack of intrinsic developmental potential and the negative outcomes of several prior attempts.


METHODS
NSCs from human fetal spinal cord were grafted into the lumbar cord of SOD1 G93A rats. The differentiation fate of grafted NSCs and their effects on motor neuron number, locomotor performance, disease onset, and survival trends/longevity were assessed. Trophic mechanisms of observed clinical effects were explored with molecular and cellular methodologies.


RESULTS
Human NSCs showed extensive differentiation into neurons that formed synaptic contacts with host nerve cells and expressed and released glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. NSC grafts delayed the onset and progression of the fulminant motor neuron disease typical of the rat SOD1 G93A model and extended the lifespan of these animals by more than 10 days, despite the restricted grafting schedule that was limited to the lumbar protuberance.


CONCLUSIONS
NSC grafts can survive well in a neurodegenerative environment and exert powerful clinical effects; at least a portion of these effects may be related to the ability of these grafts to express and release motor neuron growth factors delivered to host motor neurons via graft-host connections.
Xu
Leyan
L
Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Yan
Jun
J
Chen
David
D
Welsh
Annie M
AM
Hazel
Thomas
T
Johe
Karl
K
Hatfield
Glen
G
Koliatsos
Vassilis E
VE
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D006085:Graft Survival; D006801:Humans; D008297:Male; D016472:Motor Neuron Disease / Q000503:physiopathology / Q000628:therapy*; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D033081:Shear Strength; D013116:Spinal Cord / Q000196:embryology; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous