Neural Stem Cells RescuenervousPurkinje Neurons by Restoring Molecular Homeostasis of Tissue Plasminogen Activator and Downstream Targets

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Abstract
Neural stem cells (NSCs) offer special therapeutic prospects because they can be isolated from the CNS, expandedex 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. Innervous(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 innrcerebellum a 10-fold increase in tissue plasminogen activator (tPA) as a key component of the mechanism causingnrPN death. Here we report that undifferentiated wild-type murine NSCs, when transplanted into the newbornnrcerebellar 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 ofnrPNs also is verified by anin vitroorganotypic slice model in whichnrcerebellar slices are cocultured with NSCs. Most importantly, the integrated NSCs in youngnrcerebellum 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.