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Updated: May 23, 2026
Mesenchymal Stem Cell Regulation of Macrophage Phagocytosis; Quantitation and Imaging
Published on: July 16, 2021
Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells
Shigeki Ohta1, Aya Misawa, Raita Fukaya
1Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Japan.
Abstract:
In 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.
Insights
Macrophage migration inhibitory factor (MIF) promotes neural stem/progenitor cell (NSPC) proliferation and survival. This discovery highlights MIF as a potential therapeutic agent for treating brain disorders by activating NSPCs.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Dendritic cells (DCs) were previously shown to enhance neural stem/progenitor cell (NSPC) numbers.
- The role of macrophage migration inhibitory factor (MIF) in the brain is not well understood.
- MIF is known to bind CD74-CD44 complexes in macrophages.
Purpose of the Study:
- To identify novel factors supporting neural stem/progenitor cell (NSPC) proliferation and survival.
- To investigate the role and mechanism of macrophage migration inhibitory factor (MIF) in NSPC regulation.
- To explore the potential of MIF as a therapeutic agent for neurodegenerative diseases.
Main Methods:
- Flow cytometry to detect MIF receptor expression in mouse neurospheres.
- Analysis of CD74 expression in embryonic mouse brains.
- Assessment of MIF's effect on neurosphere formation, proliferation, and cell death (caspase 3/7 activity).
- Western blot analysis to examine signaling pathway activation (Akt, Erk, AMPK, Stat3) and gene expression (Hes3, Egfr).
- Chemotaxis assays to evaluate NSPC migration in response to MIF.
Main Results:
- Macrophage migration inhibitory factor (MIF) receptors (CD74) are expressed in mouse neurospheres and the developing brain.
- MIF significantly increased the formation and proliferation of primary and secondary neurospheres.
- MIF knockdown or inhibition suppressed neurosphere formation and proliferation, while increasing apoptosis.
- MIF activated key signaling pathways (Akt, Erk, AMPK, Stat3) and upregulated survival/proliferation genes (Hes3, Egfr).
- MIF demonstrated chemoattractant properties for NSPCs.
Conclusions:
- Macrophage migration inhibitory factor (MIF) directly supports neural stem/progenitor cell (NSPC) proliferation, survival, and maintenance.
- MIF acts through multiple synergistic signaling pathways, including Akt, Erk, AMPK, and Stat3.
- MIF represents a promising therapeutic factor for activating NSPCs in the context of degenerative brain disorders.
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