P45. Functional analysis of macrophage migration inhibitory factor (MIF) in the mouse neural stem/progenitor cells

Abstract

In previous studies, we demonstrated that mouse dendritic cells (DCs) can increase the number of neural stem/progenitor cells (NSPCs) in vitro and in vivo (JNR 2004; 76: 453–465). We identified migration inhibitory factor (MIF) that is secreted from DCs and NSPCs as a novel factor that can support the proliferation and/or survival of NSPCs in vitro, although the function of MIF in the normal brain remains largely unknown. It was previously shown that in macrophages, MIF binds to a complex of CD74 and CD44. In the present study, we observed CD74/CD44 double-positive cell population in mouse ganglionic eminence (GE)-derived neurospheres using flow cytometry technique in vitro. We further found the expression of CD74 in GE of E14 mouse brain, suggesting the functional role of MIF in vivo. MIF increased the number of primary and secondary neurospheres. In contrast, retrovirally expressed MIF shRNAi suppressed the secondary neurosphere formations, cell proliferation, and increased the caspase3/7 activity in neurospheres. Moreover, we found that in neurospheres MIF increases the phosphorylation of Akt, Erk, AMPK, and Stat3 (Ser727) which are known as factors supporting the cell survival, proliferation and/or maintenance of NSPCs. Taken together, MIF can cause proliferation and maintain NSPCs utilizing multiple-signaling pathways synergistically and may be a new therapeutic factor for brain degeneration disorders through NSPCs activation.