1. Department of Anesthesiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
Int J Biol Sci. 2013 Nov 28;9(10):1108-20. doi: 10.7150/ijbs.7232. eCollection 2013.
Macrophage migration inhibitory factor (MIF) is a highly conserved and evolutionarily ancient mediator with pleiotropic effects. Recent studies demonstrated that the receptors of MIF, including CD44, CXCR2, CXCR4 and CD74, are expressed in the neural stem/progenitor cells (NSPCs). The potential regulatory effect of MIF on NSPCs proliferation and neuronal differentiation, however, is largely unknown. Here, we investigated the effect of MIF on NSPC proliferation and neuronal differentiation, and further examined the signal pathway by which MIF transduced these signal effects in mouse NSPCs in vitro. The results showed that both Ki67-positive cells and neurosphere volumes were increased in a dose-dependent manner following MIF treatment. Furthermore, the expression of nuclear β-catenin was significantly stronger in MIF-stimulated groups than that in control groups. Conversely, administration of IWR-1, the inhibitor of Wnt/β-catenin pathway, significantly inhibited the proliferative effect of MIF on NSPCs. Immunostaining and Western blot further indicated that doublecortin (DCX) and Tuj 1, two neuronal markers, were evidently increased with MIF stimulation during NSPC differentiation, and there were more Tuj1-positive cells migrated out from neurospheres in MIF-stimulated groups than those in control groups. During NSPC differentiation, MIF increased the activity of β-galactosidase that responds to Wnt/β-catenin signaling. Wnt1 and β-catenin proteins were also up-regulated with MIF stimulation. Moreover, the expression of DCX and Tuj 1 was inhibited significantly by IWR-1. Taken together, the present study indicated that MIF enhances NSPC proliferation and promotes the neuronal differentiation, by activating Wnt/β-catenin signal pathway. The interaction between MIF and Wnt/β-catenin signal pathway may play an important role in modulating NSPC renewal and fate during brain development.
巨噬细胞移动抑制因子（MIF）是一种高度保守且在进化上古老的多效性介质。最近的研究表明，MIF 的受体，包括 CD44、CXCR2、CXCR4 和 CD74，在神经干细胞/祖细胞（NSPCs）中表达。然而，MIF 对 NSPC 增殖和神经元分化的潜在调节作用在很大程度上仍是未知的。在这里，我们研究了 MIF 对 NSPC 增殖和神经元分化的影响，并进一步研究了 MIF 在体外向 NSPC 传递这些信号作用的信号通路。结果表明，MIF 处理后，Ki67 阳性细胞和神经球体积均呈剂量依赖性增加。此外，MIF 刺激组的核 β-连环蛋白表达明显强于对照组。相反，Wnt/β-连环蛋白通路抑制剂 IWR-1 的给药显著抑制了 MIF 对 NSPC 的增殖作用。免疫染色和 Western blot 进一步表明，在 NSPC 分化过程中，MIF 刺激明显增加了双皮质素（DCX）和 Tuj1 两种神经元标志物的表达，与对照组相比，MIF 刺激组中更多的 Tuj1 阳性细胞从神经球中迁移出来。在 NSPC 分化过程中，MIF 增加了对 Wnt/β-连环蛋白信号的β-半乳糖苷酶活性。MIF 刺激也上调了 Wnt1 和 β-连环蛋白蛋白的表达。此外，IWR-1 显著抑制了 DCX 和 Tuj 1 的表达。总之，本研究表明，MIF 通过激活 Wnt/β-连环蛋白信号通路，增强 NSPC 的增殖并促进神经元分化。MIF 和 Wnt/β-连环蛋白信号通路之间的相互作用可能在调节脑发育过程中 NSPC 的更新和命运方面发挥重要作用。
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