Abstract
Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single-cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.
Highlights
Hair cells (HCs) are the auditory sensors that enable vertebrates to hear
We demonstrated that in vivo ectopic Atoh1 expression in neonatal and juvenile supporting cells (SCs) is sufficient to convert these cells into nascent HCs that express early HC markers such as Myo6 and Myo7a (Liu et al, 2012a)
We began by generating a Rosa26-CAG-Loxp-stop- Loxp-Ikzf2*3xHA-T 2A-Tdtomato/+ knock in mouse line (Rosa26CAG-LSL-Ikzf2/+ for short), in which Ikzf2 is tagged with 3× HA fragments at its C-terminus (Figure 1—figure supplement 1A–C)
Summary
Hair cells (HCs) are the auditory sensors that enable vertebrates to hear. These cells are located in the auditory epithelium, the latter referred to as the organ of Corti (OC) (Wu and Kelley, 2012). Adult PCs and DCs are not sensitive to ectopic Atoh expression (Kelly et al, 2012; Liu et al, 2012a), unless additional manipulations are performed (Walters et al, 2017) Despite this progress, no newly in vivo transformed HCs has been reported to express Prestin (Chai et al, 2012; Liu et al, 2012a; Walters et al, 2017). To the best of our knowledge, this is the first report of in vivo generation of Prestin+ OHC -like cells from adult cochlear SCs. Our findings identify Atoh and Ikzf as potential targets for OHC regeneration therapy in hearing-impaired patients. Future work is still called for as the Prestin+ OHC -like cells were still insufficiently differentiated to restore hearing loss caused by OHC damage
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