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


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 β-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (β-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.

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Figure 1: Transplantation of mNSCs into the brains of Hexb−/− mice prolongs life, delays symptom onset and preserves motor function.
Figure 2: mNSCs differentiate into a range of neural cell types in the Hexb−/− mouse cortex, including electrophysiologically active neurons.
Figure 3: Transplanted mNSCs increase Hex levels and reduce GM2 and GA2 ganglioside storage.
Figure 4: NSC transplantation interfaces with other therapeutic mechanisms.
Figure 5: Both 'primary' (CNS-derived) and 'secondary' (hESC-derived) human NSC transplantation benefit Hexb−/− mice.
Figure 6: hNSCs (derived from hESCs) stably engrafted in the Hexb−/− mouse cortex for at least 5.5 months after neonatal transplantation, differentiating into cells expressing neuronal and glial markers.


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Supported by National Tay-Sachs and Allied Diseases Association (NTSAD), Late-Onset Tay-Sachs Foundation, Children's Neurobiological Solutions, A-T Children's Project, Barbara Anderson Foundation for Brain Repair, Project ALS, March of Dimes, Hunter's Hope, Lysosomal Storage Disease Research Consortium, Neurosurgery Neuroscience Consortium, Division of Neurosurgery at the University of California, San Diego, National Institute of General Medicine, National Eye Institute, National Institute of Neurological Diseases and Stroke, National Institute of Child Health and Human Development, Korean Ministry of Science and Technology, Medical Research Council and the University of Oxford.

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Corresponding authors

Correspondence to Frances M Platt or Evan Y Snyder.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transplantation of mNSCs from clone C17.2 into the brains of SD mice significantly delayed motor deficit onset and preserved motor function when widely distributed throughout the cerebrum and cerebellum. (PDF 252 kb)

Supplementary Fig. 2

Additional low-power images of X-gal- and ββ–gal-stained thick (1mm) serial coronal sections through the brains of multiple representative adult SD mice suggest the extent of routine engraftment, the uniformity and reproducibility of results, and representative differentiation patterns. (PDF 290 kb)

Supplementary Fig. 3

NSCs from dissociated mouse and human neurospheres engraft throughout the forebrain following neonatal intraventricular transplantation. (PDF 152 kb)

Supplementary Fig. 4

mNSCs differentiated into a range of neural cell types in the SD mouse cortex. (PDF 227 kb)

Supplementary Fig. 5

Microgliosis without lymphocytosis characterizes the SD brain and is diminished by hNSC transplantation. (PDF 222 kb)

Supplementary Fig. 6

NSC transplantation and substrate reduction therapy (SRT) are synergistic in increasing life span and delaying motor deficit onset in SD mice. (PDF 422 kb)

Supplementary Table 1

A. Cell-type composition of engrafted donor human NSCs and donor-to-host cell ratios in Hexb−/−mouse cerebral cortex. B. Cell-type composition of engrafted donor mouse NSCs and donor-to-host cell ratios in Hexb−/− mouse cerebral cortex. (PDF 442 kb)

Supplementary Methods (PDF 217 kb)

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Lee, JP., Jeyakumar, M., Gonzalez, R. et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med 13, 439–447 (2007).

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