Article abstract

Nature Medicine 13, 439 - 447 (2007)
Published online: 11 March 2007 | doi:10.1038/nm1548

Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease

Jean-Pyo Lee1,2,12, Mylvaganam Jeyakumar3,12, Rodolfo Gonzalez1, Hiroto Takahashi1,11, Pei-Jen Lee1, Rena C Baek4, Dan Clark1, Heather Rose1, Gerald Fu1, Jonathan Clarke1, Scott McKercher1, Jennifer Meerloo1, Franz-Josef Muller1,5, Kook In Park6, Terry D Butters3, Raymond A Dwek3, Philip Schwartz7, Gang Tong1,8, David Wenger9, Stuart A Lipton1,8, Thomas N Seyfried4, Frances M Platt3 & Evan Y Snyder1,2,10

Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.

  1. Stem Cell & Regeneration Program, Center for Neuroscience and Aging Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
  2. Department of Pediatrics, University of California San Diego, School of Medicine, La Jolla, California 92093, USA.
  3. Department of Biochemistry, Glycobiology Institute, University of Oxford, Oxford OX1 3QU, UK.
  4. Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, USA.
  5. Zentrum für Integrative Psychiatrie, Kiel 24105, Germany.
  6. Department of Pediatrics, Yonsei University College of Medicine, Seoul 120-749, Korea.
  7. Children's Hospital of Orange County Research Institute, Orange, California 92826, USA.
  8. Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093, USA.
  9. Department of Neurology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
  10. San Diego Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
  11. Present address: Janelia Farm Research Campus, Ashburn, Virginia 20147, USA.
  12. These authors contributed equally to this work.

Correspondence to: Evan Y Snyder1,2,10 e-mail:

Correspondence to: Frances M Platt3 e-mail: