Mouse Embryonic Stem Cells Differentiated into Neuron-like Cells or Schwann Cell-like Cells for the Development of Strategies to Ameliorate Deafness.

Abstract

Cochlear prostheses (CI) can restore hearing to patients with extensive sensorineural hearing loss (SNHL) by replacing lost or damaged cochlear mechanosensory hair cells (HC) with an electrode array. For the CI to send meaningful acoustic information to the brain, as large a population of remaining inner ear spiral ganglion neurons (SGN) as possible must become functionally coupled to the CI. SGN-CI coupling would be enhanced by a means of inducing directed neurite extension from the remaining SGN to the CI. Macrophage migration inhibitory factor (MIF) is a neurotrophic cytokine, which is expressed in early embryogenesis in the central and peripheral nervous systems, the eye and inner ear, where it is expressed in the supporting cells that underlie the HC and in all Schwann Cells. We produced a mESC-derived neuron-like population of cells from mESC exposed to recombinant MIF that in many respects resemble SGN. Maturation of these MIF mESC-derived neuron-like cells was enhanced by Docosahexaenoic acid, a fatty acid that helps promote neuronal maturation. Such cells could be used eventually to replace lost of damaged SGN. This laboratory also produced the first embryonic stem cell (ESC) derived model of the Schwann Cell. These Schwann cells produce MIF, which is capable of inducing directional neurite outgrowth and supporting the survival of both early stage statoacoustic ganglion neurons (SAG) and their adult counterparts in the SGN as do all Schwann Cells. We have coated CIs with mESC-MIF-producing “Schwann Cells” and observed directional outgrowth and contact formation between the “Schwann Cell”-coated CI and primary mouse embryonic SAG or adult SGN to bring the neurites closer to the CI for better performance. Thus two different stem cell-based approaches have been used to address two different problems in deafness: improved integration of CI with native SGN and replacement of SGN themselves with a stem cell population molecularly engineered to resemble SGN.