Abstract
Induced pluripotent stem cells (iPSCs) may serve as an autologous source of replacement neurons in the injured cochlea, if they can be successfully differentiated and reconnected with residual elements in the damaged auditory system. Here, we explored the potential of hiPSC-derived neurons to innervate early postnatal hair cells, using established in vitro assays. We compared two hiPSC lines against a well-characterized hESC line. After ten days' coculture in vitro, hiPSC-derived neural processes contacted inner and outer hair cells in whole cochlear explant cultures. Neural processes from hiPSC-derived neurons also made contact with hair cells in denervated sensory epithelia explants and expressed synapsin at these points of contact. Interestingly, hiPSC-derived neurons cocultured with hair cells at an early stage of differentiation formed synapses with a higher number of hair cells, compared to hiPSC-derived neurons cocultured at a later stage of differentiation. Notable differences in the innervation potentials of the hiPSC-derived neurons were also observed and variations existed between the hiPSC lines in their innervation efficiencies. Collectively, these data illustrate the promise of hiPSCs for auditory neuron replacement and highlight the need to develop methods to mitigate variabilities observed amongst hiPSC lines, in order to achieve reliable clinical improvements for patients.
Highlights
The Auditory neuron hiPSC (AN) are responsible for faithfully transmitting acoustic information from the inner ear to the brain
In order to investigate whether hiPSC-derived neurons could contact their peripheral targets, 21 DIV neural progenitors derived from two hiPSC lines and one Human embryonic stem cells DIV (hESCs) (H9; control) line were cocultured with postnatal day 3/4 (P3/4) whole cochlear explants (Figure 2(a))
There was no significant difference in the average number of hair cells that the iPS1 and iPS2 cell lines were contacting throughout the cocultures examined (p = 0.38; Figure 2(f))
Summary
The ANs are responsible for faithfully transmitting acoustic information from the inner ear to the brain. The cell bodies of these neurons reside in a bony channel called Rosenthal’s canal, which is located in the middle (modiolus) of the cochlea. Each of these cell bodies extends a peripheral process towards the organ of Corti to innervate the sensory hair cells, while the central processes project into the auditory nerve and synapse with neurons in the cochlear nucleus. A variety of measures have been explored over the last two decades to restore or replace the damaged ANs following hearing loss, one being the use of stem cells. In order for stem cells to be used as a therapy for AN replacement, it is important that the donor cells are derived from a suitable source and are capable of innervating the appropriate cells/tissues in the peripheral and central auditory system [3]
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