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The Journal of Neuroscience, July 26, 2006, 26(30):7839-7848; doi:10.1523/JNEUROSCI.1624-06.2006

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Neurobiology of Disease
Neural Stem Cells Rescue nervous Purkinje Neurons by Restoring Molecular Homeostasis of Tissue Plasminogen Activator and Downstream Targets

Jianxue Li,¹ Jaime Imitola,² Evan Y. Snyder,³ and Richard L. Sidman¹

¹Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, ²Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ³Stem Cell and Regeneration Program, the Burnham Institute for Medical Research, La Jolla, California 92037

Correspondence should be addressed to either of the following: Richard L. Sidman, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine 838, Boston, MA 02115, richard_sidman{at}hms.harvard.edu; or Evan Y. Snyder, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, esnyder{at}burnham.org

Neural stem cells (NSCs) offer special therapeutic prospects because they can be isolated from the CNS, expanded ex vivo, and re-implanted into diseased CNS where they not only migrate and differentiate according to cues from host tissue but also appear to be capable of affecting host cells. In nervous (nr) mutant mice Purkinje neuron (PN) mitochondria become abnormal by the second postnatal week, and a majority of PNs die in the fourth to fifth weeks. We previously identified in nr cerebellum a 10-fold increase in tissue plasminogen activator (tPA) as a key component of the mechanism causing nr PN death. Here we report that undifferentiated wild-type murine NSCs, when transplanted into the newborn nr cerebellar cortex, do not replace host PNs but contact imperiled PNs and support their mitochondrial function, dendritic growth, and synaptogenesis, subsequently leading to the rescue of host PNs and restoration of motor coordination. This protection of nr PNs also is verified by an in vitro organotypic slice model in which nr cerebellar slices are cocultured with NSCs. Most importantly, the integrated NSCs in young nr cerebellum rectify excessive tPA mRNA and protein to close to normal levels and protect the mitochondrial voltage-dependent anion channel and neurotrophins, downstream targets of the tPA/plasmin proteolytic system. This report demonstrates for the first time that NSCs can rescue imperiled host neurons by rectifying their gene expression, elevating somatic stem cell therapeutic potential beyond solely cell replacement strategy.

Key words: neural stem cell; Purkinje neuron degeneration; cell rescue; tissue plasminogen activator; mitochondria; neurotrophin

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Received April 14, 2006; revised June 17, 2006; accepted June 20, 2006.

Correspondence should be addressed to either of the following: Richard L. Sidman, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine 838, Boston, MA 02115, richard_sidman{at}hms.harvard.edu; or Evan Y. Snyder, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, esnyder{at}burnham.org

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