Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells

Abstract

SummaryIn a previous study, we showed that murine dendritic cells (DCs) can increase the number of neural stem/progenitor cells (NSPCs) in vitro and in vivo. In the present study, we identified macrophage migration inhibitory factor (MIF) as a novel factor that can support the proliferation and/or survival of NSPCs in vitro. MIF is secreted by DCs and NSPCs, and its function in the normal brain remains largely unknown. It was previously shown that in macrophages, MIF binds to a CD74-CD44 complex. In the present study, we observed the expression of MIF receptors in mouse ganglionic-eminence-derived neurospheres using flow cytometry in vitro. We also found CD74 expression in the ganglionic eminence of E14 mouse brains, suggesting that MIF plays a physiological role in vivo. MIF increased the number of primary and secondary neurospheres. By contrast, retrovirally expressed MIF shRNA and MIF inhibitor (ISO-1) suppressed primary and secondary neurosphere formation, as well as cell proliferation. In the neurospheres, MIF knockdown by shRNA increased caspase 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 chemoattractant for NSPCs. These results show that MIF can induce NSPC proliferation and maintenance by multiple signaling pathways acting synergistically, and it may be a potential therapeutic factor, capable of activating NSPC, for the treatment of degenerative brain disorders.

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

“…We screen several neuronal-and glial cell-(including RG) secreted molecules that might have the potential to induce microglia proliferation. Among them, we concentrated on MIF 38,39 , since it has been consistently shown that this cytokine can modulate myeloid cell proliferation by binding to the CD74 receptor 40 . By in situ hybridization we detected MIF mRNA in germinal niches of the developing cerebral cortex at E12.5, E14.5, E16.5 and E18.5.…”

MIF Maintains the Tumorigenic Capacity of Brain Tumor–Initiating Cells by Directly Inhibiting p53

“…MIF is a cancer-related gene that has previously been shown to promote cell survival and proliferation in mouse NSCs (40). Intriguingly, the MIF ( Fig.…”

Macrophage Migration Inhibitory Factor Limits Activation-Induced Apoptosis of Platelets via CXCR7-Dependent Akt Signaling

“…MIF is thus a pivotal regulator of atherogenesis and also plaque vulnerability. [10][11][12] MIF is associated with extensive lesion development, 12,13 whereas blocking MIF or its genetic deletion reduces macrophage and T-cell content in atherosclerotic plaques and attenuates atheroprogression in ApoE −/− mice.…”

“…[11][12][13][14][15] Because most of these diseases are ameliorated by either genetic deletion of Mif or MIF neutralization, anti-MIF therapies have raised significant clinical interest. MIF levels in plasma are enhanced in patients with acute myocardial infarction and associated with inflammatory markers C-reactive protein and IL-6 and correlate with cardiac necrosis marker troponin I release.…”