Microglial activation mediates host neuronal survival induced by neural stem cells

The rational of neural stem cells ( NSC s) in the therapy of neurological disease is either to replace dead neurons or to improve host neuronal survival, the latter of which has got less attention and the underlying mechanism is as yet little known. Using a transwell co‐culture system, we reported that, in organotypic brain slice cultures, NSC s significantly improved host neuronal viability. Interestingly, this beneficial effect of NSC s was abrogated by a microglial inhibitor minocycline, while it was mimicked by a microglial agonist, Toll‐like receptor 9 ( TLR 9) ligand CpG‐ ODN , which supports the pro‐vital mediation by microglia on this NSC s‐improved neuronal survival. Moreover, we showed that NSC s significantly induced host microglial movement and higher expression of a microglial marker IBA ‐1, the latter of which was positively correlated with TLR 9 or extracellular‐regulated protein kinases 1/2 ( ERK 1/2) activation. Real‐time PCR revealed that NSC s inhibited the expression of pro‐inflammatory molecules, but significantly increased the expression of molecules associated with a neuroprotective phenotype such as CX 3 CR 1, triggering receptor expressed on myeloid cells‐2 ( TREM 2) and insulin growth factor 1 ( IGF ‐1). Similarly, in the microglia cells, NSC s induced the same microglial response as that in the slices. Further treatment with TLR 9 ligand CpG‐ ODN , TLR 9 inhibitor chloroquine ( CQ ) or ERK 1/2 inhibitor U0126 demonstrated that TLR 9‐ ERK 1/2 pathway was involved in the NSC s‐induced microglial activation. Collectively, this study indicated that NSC s improve host neuronal survival by switching microglia from a detrimental to a neuroprotective phenotype in adult mouse brain, and the microglial TLR 9‐ ERK 1/2 pathway seems to participate in this NSC s‐mediated rescue action.