Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc. Natl. Acad. Sci. USA 101, 18117–18122 (2004).
Flax, J.D. et al. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat. Biotechnol. 16, 1033–1039 (1998).
Snyder, E.Y., Taylor, R.M. & Wolfe, J.H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367–370 (1995).
Martinez-Serrano, A., Fischer, W. & Bjorklund, A. Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 15, 473–484 (1995).
Park, K.I., Teng, Y.D. & Snyder, E.Y. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat. Biotechnol. 20, 1111–1117 (2002).
Givogri, M.I. et al. Oligodendroglial progenitor cell therapy limits central neurological deficits in mice with metachromatic leukodystrophy. J. Neurosci. 26, 3109–3119 (2006).
Kondo, Y., Wenger, D.A., Gallo, V. & Duncan, I.D. Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice. Proc. Natl. Acad. Sci. USA 102, 18670–18675 (2005).
Sango, K. et al. Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nat. Genet. 14, 348–352 (1996).
Wada, R., Tifft, C.J. & Proia, R.L. Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc. Natl. Acad. Sci. USA 97, 10954–10959 (2000).
Myerowitz, R. et al. Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum. Mol. Genet. 11, 1343–1350 (2002).
Jeyakumar, M. et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126, 974–987 (2003).
Park, K. et al. Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: evidence from the effect of hypoxia-ischemia in the CNS on clonal “reporter” neural stem cells. Exp. Neurol. 199, 156–178 (2006).
Parker, M.A. et al. Expression profile of an operationally-defined neural stem cell clone. Exp. Neurol. 194, 320–332 (2005).
Cartwright, P. et al. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132, 885–896 (2005).
Light, W., Vernon, A.E., Lasorella, A., Iavarone, A. & LaBonne, C. Xenopus Id3 is required downstream of Myc for the formation of multipotent neural crest progenitor cells. Development 132, 1831–1841 (2005).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Maragakis, N.J. et al. Glial restricted precursors protect against chronic glutamate neurotoxicity of motor neurons in vitro. Glia 50, 145–159 (2005).
Murphy, M.J., Wilson, A. & Trumpp, A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 15, 128–137 (2005).
Jeyakumar, M. et al. Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc. Natl. Acad. Sci. USA 96, 6388–6393 (1999).
Rosario, C.M. et al. Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development 124, 4213–4224 (1997).
Lacorazza, H.D., Flax, J.D., Snyder, E.Y. & Jendoubi, M. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat. Med. 2, 424–429 (1996).
Hultberg, B., Isaksson, A., Nordstrom, M. & Kjellstrom, T. Release of beta-hexosaminidase isoenzymes in cultured human fibroblasts. Clin. Chim. Acta 216, 73–79 (1993).
Conzelmann, E. & Sandhoff, K. Partial enzyme deficiencies: residual activities and the development of neurological disorders. Dev. Neurosci. 6, 58–71 (1983).
Teng, Y.D. et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc. Natl. Acad. Sci. USA 99, 3024–3029 (2002).
Tifft, C.J. & Proia, R.L. Stemming the tide: glycosphingolipid synthesis inhibitors as therapy for storage diseases. Glycobiology 10, 1249–1258 (2000).
Platt, F.M. et al. Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276, 428–431 (1997).
Kasperzyk, J.L. et al. N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J. Neurochem. 89, 645–653 (2004).
Andersson, U. et al. Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. Neurobiol. Dis. 16, 506–515 (2004).
Davison, A.C. & Hinkley, D.V. Bootstrap Methods and Their Application. (Cambridge Univ. Press, Cambridge, UK, 2003).
Pellegatta, S. et al. The therapeutic potential of neural stem/progenitor cells in murine globoid cell leukodystrophy is conditioned by macrophage/microglia activation. Neurobiol. Dis. 21, 314–323 (2006).
Wu, Y.P. & Proia, R.L. Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proc. Natl. Acad. Sci. USA 101, 8425–8430 (2004).
Jeyakumar, M. et al. NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin. Ann. Neurol. 56, 642–649 (2004).
Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).
Gravel, R.A. et al. The GM2 gangliosidoses. in The Metabolic and Molecular Bases of Inherited Disease (eds. Scriver, C.R., Beaudet, A.L., Valle, D. & Sly, W.S.) 3827–3876 (McGraw-Hill, New York, 2001).
Cachon-Gonzalez, M.B. et al. Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc. Natl. Acad. Sci. USA 103, 10373–10378 (2006).
Roy, N.S. et al. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12, 1259–1268 (2006).
Zhang, S.C., Wernig, M., Duncan, I.D., Brustle, O. & Thomson, J.A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129–1133 (2001).
Svendsen, C.N. et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp. Neurol. 148, 135–146 (1997).
Muotri, A.R., Nakashima, K., Toni, N., Sandler, V.M. & Gage, F.H. Development of functional human embryonic stem cell-derived neurons in mouse brain. Proc. Natl. Acad. Sci. USA 102, 18644–18648 (2005).
Knoepfler, P.S., Cheng, P.F. & Eisenman, R.N. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. Genes Dev. 16, 2699–2712 (2002).
Reynolds, B.A. & Rietze, R.L. Neural stem cells and neurospheres–re-evaluating the relationship. Nat. Methods 2, 333–336 (2005).
Schwartz, P.H. et al. Isolation and characterization of neural progenitor cells from post-mortem human cortex. J. Neurosci. Res. 74, 838–851 (2003).
Ourednik, V. et al. Segregation of human neural stem cells in the developing primate forebrain. Science 293, 1820–1824 (2001).
Carpenter, M.K. et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp. Neurol. 172, 383–397 (2001).
Reubinoff, B.E. et al. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 19, 1134–1140 (2001).
Coggeshall, R.E. & Lekan, H.A. Methods for determining numbers of cells and synapses: a case for more uniform standards of review. J. Comp. Neurol. 364, 6–15 (1996).
Guillery, R.W. & Herrup, K. Quantification without pontification: choosing a method for counting objects in sectioned tissues. J. Comp. Neurol. 386, 2–7 (1997).
Stuart, G.J., Dodt, H.U. & Sakmann, B. Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pflugers Arch. 423, 511–518 (1993).
Wenger, D.A. & Williams, C. Screening for lysosomal disorders. in Techniques in Diagnostic Human Biochemical Genetics. A Laboratory Manual (ed. Hommes, F.A.) 587–617 (Wiley-Liss, New York, 1991).
Neville, D.C. et al. Analysis of fluorescently labeled glycosphingolipid-derived oligosaccharides following ceramide glycanase digestion and anthranilic acid labeling. Anal. Biochem. 331, 275–282 (2004).
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
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)
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/nm1548
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1548
This article is cited by
-
Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury
Scientific Reports (2023)
-
KAP1 phosphorylation promotes the survival of neural stem cells after ischemia/reperfusion by maintaining the stability of PCNA
Stem Cell Research & Therapy (2022)
-
Blood–brain barrier: emerging trends on transport models and new-age strategies for therapeutics intervention against neurological disorders
Molecular Brain (2022)
-
Sphingolipid lysosomal storage diseases: from bench to bedside
Lipids in Health and Disease (2021)
-
Prenatal transplantation of human amniotic fluid stem cell could improve clinical outcome of type III spinal muscular atrophy in mice
Scientific Reports (2021)