Extracellular Matrix and Hearing Function: Role of Hyaluronic Acid

Hyaluronic acid (HA), a non-sulfated glycosaminoglycan, is part of the ground substance, a gel-like structure that bathes all the ECM components. HA has been involved both in tissue biomechanics, as it awards visco-elastic properties, and in cell signaling, through cell-ECM receptors. Thus, HA takes part in several biological processes, including morphogenesis and inflammation. Multiple studies demonstrated the importance of ECM during inner ear development and in hearing and some HA-related genes have been associated with hearing impairments. As such, the gene Cemip (or KIAA1199), encoding a Hyaluronidase, has been reported to be mutated in deaf patients. We therefore aim at characterizing the role of HA in hearing function.

By combining specific immunostainings, RNAscope and qRT-PCR assays, we first explored the spatio-temporal distribution of cochlear HA as well as the expression profile of enzymes responsible for its synthesis and degradation. In addition, we generated a mutant mouse model in which Cemip gene has been invalidated. We took advantage of this model to investigate the impact of HA accumulation on cochlear morphogenesis and hearing function, by performing morphological analyses and Auditory Brainstem Response (ABR) recordings.

We found that HA is highly enriched in the basilar membrane (BM), for which visco-elastic properties are instrumental in sound wave decomposition, frequency discrimination and mechanical sound wave conversion. The main enzymes involved in HA metabolism are present at embryonic and postnatal stages in the cochlear duct and in the spiral ganglion. Despite an accumulation of HA in the BM region below hair cells, the global morphology of Cemip-deficient cochleae is preserved, suggesting that Cemip has no prominent role in cochlear development. However, we evidenced that hearing function of Cemip KO mice is slightly impaired, as ABR recordings revealed an increase in peak 1 amplitude at some frequencies. Although unexpected, this result suggests that either more sensory cells are stimulated by sound, or that spiral ganglion neurons are over-activated compared to control mice.

Altogether, our data suggest that HA might be instrumental in cochlear biomechanics, by awarding visco-elastic properties to the BM. Cemip loss has no critical impact on cochlear development and hearing, although an overstimulation of the cochlear nerve has been observed. We are currently investigating further this phenotype to identify the cause of this neuronal over-stimulation and we particularly focus on BM morphology and cochlear perineuronal nets. In the future, we also plan to examine whether Cemip KO mice are more prone to noise-induced hearing loss due to neuron excitotoxicity, for example.