Macrophage migration inhibitory factor acts as a neurotrophin in the developing inner ear

Concomitant differentiation of a population of mouse embryonic stem cells into neuron‐like cells and schwann cell–like cells in a slow‐flow microfluidic device

“…Once we had convincing data confirming our earlier studies that MIF appears to be involved in directional neurite outgrowth either through its direct effects (see Fig. 1 in Bank et al, 2012) or through its production by a mouse embryonic stem cell (mESC)derived "Schwann cell" lawn (see Fig. 5B in Roth et al, 2007), we used the MIF-producing mESC-derived Schwann cells, encapsulated in sodium alginate hydrogels, to coat two types of cochlear implants: the multi-electrode type commonly used in human patients and the simple ball type used in animal studies.…”

“…When macrophage migration inhibitory factor (MIF)-and not nerve growth factor (NGF) or ciliary neurotrophic factor (CNTF)is the neuron-inducing agent, we show that the neuron-like cells bear some significant resemblance to statoacoustic ganglion or SGNs of the inner ear. NGF and CNTF also induce neuronal phenotypes: We have shown in other studies that NGF produces dorsal root ganglion-like neurons and CNTF induced motor neuronlike neurons Roth et al, 2008;Bank et al, 2012). We have previously shown that MIF is the inner ear's first developmentally important neurotrophin (Holmes et al, 2011;Shen et al, 2012;Bank et al, 2012, cited in Faculty of 1000) and that receptors for MIF remain on SGNs into adulthood (Bank et al, 2012).…”

“…NGF and CNTF also induce neuronal phenotypes: We have shown in other studies that NGF produces dorsal root ganglion-like neurons and CNTF induced motor neuronlike neurons Roth et al, 2008;Bank et al, 2012). We have previously shown that MIF is the inner ear's first developmentally important neurotrophin (Holmes et al, 2011;Shen et al, 2012;Bank et al, 2012, cited in Faculty of 1000) and that receptors for MIF remain on SGNs into adulthood (Bank et al, 2012). These earlier studies were done in conventional tissue culture devices/dishes.…”

“…The gradient flow illustration (b) and microfluidic chip channel dimensions (d) are adapted from Park et al, 2009. have done previously . In another set of experiments, we blocked MIF downstream pathways with a monoclonal antibody to MIF using conditions we previously established for studies of both mouse-and chick-cultured primary neurons and stem cell-derived neurons (Bank et al, 2012). Blocking MIF resulted in a significant reduction in directional neurite outgrowth toward the "Schwann cell" lawn in the microfluidic devices ( Fig.…”

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Background: To send meaningful information to the brain, an inner ear cochlear implant (CI) must become closely coupled to as large and healthy a population of remaining spiral ganglion neurons (SGN) as possible. Inner ear gangliogenesis depends on macrophage migration inhibitory factor (MIF), a directionally attractant neurotrophic cytokine made by both Schwann and supporting cells (Bank et al, 2012). MIF-induced mouse embryonic stem cell (mESC)-derived "neurons" could potentially substitute for lost or damaged SGN.

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