SPECIAL ISSUE Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non-autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy Roseanne M. Taylor,* Jean Pyo Lee,  , à James J. Palacino,à Kate A. Bower,à Jianxue Li,à Marie T. Vanier,§ David A. Wenger,– Richard L. Sidmanà and Evan Y. Snyder  , à *Department of Animal Science, Faculty of Veterinary Science, University of Sydney and New South Wales, Australia  Program in Stem Cells and Regeneration, Burnham Institute for Medical Research, La Jolla, California, USA àDepartment of Neurology, Beth Israel Deaconess Medical Center and Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA §INSERM 189, Lyon-Sud Medical School, Oullins, France and Fondation Gillet-Me ´rieux, Lyon-Sud Hospital, Pierre-Be ´nite, France –Department of Neurology, Jefferson Medical College, Philadelphia, Pennsylvania, USA Abstract While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typ- ically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a ‘sick’ cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the twitcher (twi ) mouse – as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model – loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. Twi mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine-filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile/young adult twi mice, we have determined that widespread oligodendrocyte replace- ment and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine – more so in their undif- ferentiated state than when directed ex vivo to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over-express GalC. Some twi mice grafted with such engineered NSCs had thicker white tracts and lived 2–3 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in twi mice that Received May 3, 2006; revised manuscript received May 4, 2006; accepted May 4, 2006. Address correspondence and reprint requests to Evan Y. Snyder, Program in Stem Cells and Regeneration, Burnham Institute for Medical Research, La Jolla, CA 92037, USA. E-mail: esnyder@burnham.org Abbreviations used: bFGF, basic fibroblast growth factor; GalC, gal- actocerebrosidase; GLD, globoid cell leukodystrophy; hNSCs, human neural stem cells; LSD, lysosomal storage disease; MBP, myelin basic protein; NSCs, neural stem cells; SVZ, subventricular germinal zone; twi, twitcher mouse; shi, shiverer mouse; Xgal, 5-bromo-4-chloro-3- indolyl-6D-galactoside. Journal of Neurochemistry , 2006, 97, 1585–1599 doi:10.1111/j.1471-4159.2006.03986.x Ó 2006 The Authors Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2006) 97, 1585–1599 1585