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.
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.
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.
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.
1Department of Pathology, Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, MD.
2Neuralstem, Inc., Rockville, MD.
3Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Medical Institutions, Baltimore, MD.
4Department of Neuroscience, The Johns Hopkins Medical Institutions, Baltimore, MD.
5Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, MD.
L. Xu and J. Yan contributed equally to this work.
This work was supported by National Institutes of Health grant RO1 NS045140-03, the Muscular Dystrophy Association, and the Robert Packard Center for ALS Research at Johns Hopkins.
6Address correspondence to: Vassilis E. Koliatsos, M.D., Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 558, Baltimore, MD 21205.
Received 31 March 2006. Revision requested 30 May 2006.
Accepted 7 June 2006.