Mesenchymal stem cells (MSC) promote functional recovery in experimental models 
of central nervous system (CNS) pathology and are currently being tested in 
clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial 
effects are attributed to the activation of endogenous CNS protection and repair 
processes as well as immune regulation but their mechanisms of action are poorly 
understood. Here we investigated the neuroprotective effects of mouse MSC in 
rodent MSC-neuron co-cultures and mice using models of glutamate excitotoxicity. 
A 24h pre-culture of mouse primary cortical neurons with MSC protected them 
against glutamate (NMDA) receptor-induced death and conditioned medium from MSC 
(MSC CM) was sufficient for this effect. Protection by MSC CM was associated 
with reduced mRNA levels of genes encoding NMDA receptor subunits, and increased 
levels for genes associated with non-neuronal and stem cell types, as shown by 
RT-PCR and cDNA microarray analyses. Changes in gene expression were not 
associated with alterations in cell lineage representation within the cultures. 
Further, MSC CM-mediated neuroprotection in rat retinal ganglion cells was 
associated with reduced glutamate-induced calcium influx. The adoptive transfer 
of EGFP(+)MSC in a mouse kainic acid epilepsy model also provided 
neuroprotection against glutamate excitotoxicity in vivo, as shown by reduced 
neuron damage and glial cell activation in the hippocampus. These results show 
that MSC mediate direct neuroprotection by reducing neuronal sensitivity to 
glutamate receptor ligands and altering gene expression, and suggest a link 
between the therapeutic effects of MSC and the activation of cell plasticity in 
the damaged CNS.