RT Journal Article SR Electronic T1 Neural Stem Cells Rescue nervous Purkinje Neurons by Restoring Molecular Homeostasis of Tissue Plasminogen Activator and Downstream Targets JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 7839 OP 7848 DO 10.1523/JNEUROSCI.1624-06.2006 VO 26 IS 30 A1 Jianxue Li A1 Jaime Imitola A1 Evan Y. Snyder A1 Richard L. Sidman YR 2006 UL http://www.jneurosci.org/content/26/30/7839.abstract AB 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.