In a previous study, we showed that murine dendritic cells (DCs) can increase the number of neural stem/progenitor cells (NSPCs) in vitroand in vivo. In the present study, we identified macrophage migration inhibitory factor (MIF) as a novel factor that can support theproliferation and/or survival of NSPCs in vitro. MIF is secreted by DCs and NSPCs, and its function in the normal brain remains largelyunknown. It was previously shown that in macrophages, MIF binds to a CD74–CD44 complex. In the present study, we observed theexpression of MIF receptors in mouse ganglionic-eminence-derived neurospheres using flow cytometry in vitro. We also found CD74expression in the ganglionic eminence of E14 mouse brains, suggesting that MIF plays a physiological role in vivo. MIF increased thenumber of primary and secondary neurospheres. By contrast, retrovirally expressed MIF shRNA and MIF inhibitor (ISO-1) suppressedprimary and secondary neurosphere formation, as well as cell proliferation. In the neurospheres, MIF knockdown by shRNA increasedcaspase 3/7 activity, and MIF increased the phosphorylation of Akt, Erk, AMPK and Stat3 (Ser727), as well as expression of Hes3 and Egfr,the products of which are known to support cell survival, proliferation and/or maintenance of NSPCs. MIF also acted as a chemoattractantfor NSPCs. These results show that MIF can induce NSPC proliferation and maintenance by multiple signaling pathways actingsynergistically, and it may be a potential therapeutic factor, capable of activating NSPC, for the treatment of degenerative brain disorders.
Sox6 Up-Regulation by Macrophage Migration Inhibitory Factor Promotes Survival and Maintenance of Mouse Neural Stem/Progenitor Cells
