Alan Gi-Lun Cheng

Hearing loss and dizziness are the most common sensory disorders worldwide. About 5% of the world’s population is affected by disabling hearing loss, and the prevalence is projected to increase over the next several decades. Cochlear hair cells are essential in converting sound vibrations into electrical signals, which are then relayed centrally via the spiral ganglion neurons and lead to sound perception. The irreversible loss of cochlear hair cells is the most common pathology underlying sensorineural hearing loss in humans. In stark contrast, nonmammalian species such as chicken and zebrafish spontaneously regenerate hair cells from endogenous supporting cells after hair cell damage, and the mechanisms of this process are starting to be revealed. Advances in the understanding of inner ear hair cell development have led to novel protocols to efficiently generate mouse and human inner ear organoids. Several new and promising reprogramming approaches have recently been established to induce hair cell regeneration in the mature mouse cochlear and vestibular organs. In this review, we will discuss these recent advances, the implications for treatments for human hearing loss and balance dysfunction, and future directions of the field.

Cochlear hair cells are precisely oriented by planar cell polarity. Wnt proteins direct planar cell polarity in vertebrates, but their roles in regulating cochlear planar cell polarity remain unclear. Here, we inhibit Wnt secretion by ablating epithelial Wntless and find shortened cochlea, mild hair cell misorientation and mislocalization of core planar cell polarity proteins, Fzd6 and Dvl2. Computational analysis predicts that epithelial Wnts (Wnt5a, Wnt7a, Wnt7b) and Wnt5a from surrounding periotic mesenchyme act on developing hair cells. Deletion of epithelial Wnt5a, Wnt7a, and Wnt7b additively shortens the cochlea without causing hair cell misorientation or Fzd6/Dvl2 mislocalization. Moreover, deletion of epithelial or both epithelial and mesenchymal Wnt5a fails to cause polarity defects. However, ablating both epithelial and mesenchymal Wntless severely shortens the cochlea and causes hair cell misorientation and mislocalized core planar cell polarity proteins. Thus, Wnts serve as global instructive cues directing cochlear outgrowth and hair cell polarization, with remarkable redundancy of distinct Wnts across epithelial and mesenchymal compartments to ensure a fail-safe developmental program.

The neonatal cochlear epithelium harbors regenerative capacity, attributable to the transient greater epithelial ridge (GER). After injury, GER cells re-enter the cell cycle, migrate into the damaged organ of Corti, and differentiate into sensory or supporting cells in vivo; in culture, they proliferate to form inner ear organoids. The mechanisms underlying this competence remain unclear. Here, we generated organoids from mouse GER cells and performed single-cell transcriptomics at organoid initiation. Analysis revealed extracellular matrix reorganization with prominent involvement of galectins. Functional assays combining inhibition and overexpression demonstrated that galectin-1 and Myc are both necessary and sufficient for organoid growth. Moreover, Myc overexpression conferred organoid-forming capacity in post-neonatal cochlear epithelial cells after hearing onset, thereby extending the time window for regenerative competence. In vivo, organ of Corti ablation induced galectin-1 upregulation and GER proliferation, suppressed by galectin-1 blockade, establishing a model to rekindle proliferative potential in mature cochlear cells.

The neonatal cochlear epithelium harbors regenerative capacity, attributable to the transient greater epithelial ridge (GER). After injury, GER cells re-enter the cell cycle, migrate into the damaged organ of Corti, and differentiate into sensory or supporting cells in vivo ; in culture, they proliferate to form inner ear organoids. The mechanisms underlying this competence remain unclear. Here, we generated organoids from mouse GER cells and performed single-cell transcriptomics at organoid initiation. Analysis revealed extracellular matrix reorganization with prominent involvement of galectins. Functional assays combining inhibition and overexpression demonstrated that galectin-1 and Myc are both necessary and sufficient for organoid growth. Moreover, Myc overexpression conferred organoid-forming capacity in post-neonatal cochlear epithelial cells after hearing onset, thereby extending the time window for regenerative competence. In vivo , organ of Corti ablation induced galectin-1 upregulation and GER proliferation, suppressed by galectin-1 blockade, establishing a model to rekindle proliferative potential in mature cochlear cells.

Objective: In July 2019, the Food and Drug Administration (FDA) approved unilateral cochlear implantation (CI) in children aged 5 years and older with single‐sided deafness (SSD). In this study, we evaluate how the care of children with SSD evolved after this approval. Methods: We retrospectively reviewed cases at our center (January 2014 to April 2025) of patients ages 0–21 years with SSD who received magnetic resonance imaging (MRI) and/or CT. We collected data on demographics, diagnostic workup via imaging, and hearing interventions, including CI. Results: In our cohort of 184 children with congenital SSD, 108 (58.7%) were imaged before July 2019, and in our cohort of 63 children with acquired SSD, 36 (57.1%) were imaged before July 2019. A greater proportion of children < 5 years were imaged with MRI after July 2019 in both congenital (54.6% before vs. 93.4% after, p < 0.001) and acquired SSD cohorts (42.9% before vs. 100% after, p = 0.02). The prevalence of cochlear nerve deficiency (CND) in the congenital SSD cohort was 70.4% pre‐July 2019 and 63.2% post‐July 2019. The rate of CI did not significantly increase post‐July 2019 (2.8% pre‐July 2019 vs. 3.9% post‐July 2019, p = 0.66) in our cohort of congenital SSD but did increase substantially in children with acquired SSD (2.8% pre‐July 2019 vs. 37% post‐July 2019, p < 0.001). Conclusion: Increased workup with MRI was observed after changes in FDA indications for SSD. A high proportion of CND was detected in children with congenital SSD that may affect candidacy of CI relative to children with acquired SSD, who had a significant increase in CI post‐July 2019. Level of Evidence: IV.

Cochlear hair cells are crucial for sound transduction and are precisely oriented by planar cell polarity (PCP). Wnt proteins direct PCP in vertebrates, but their roles in regulating cochlear PCP remain unclear. Here, we inhibited Wnt secretion by ablating Wntless in the cochlear epithelium and found shortened cochlea, mild hair cell misorientation and mislocalization of PCP proteins, Fzd6 and Dvl2, representing defects less severe than classic PCP mutants. Computational cell-communication analysis predicted that candidate Wnts from the cochlear epithelium (Wnt5a, Wnt7a, Wnt7b) and surrounding periotic mesenchyme (Wnt5a) act on developing hair cells. Deletion of Wnt5a, Wnt7a, and Wnt7b additively shortened the cochlea without causing hair cell misorientation or mislocalization of PCP proteins. Moreover, deletion of Wnt5a alone in the periotic mesenchyme failed to cause PCP defects. However, ablating both epithelial and mesenchymal Wnts caused a severely shortened cochlea with apically malrotated hair cells devoid of polarized core PCP proteins. Thus, Wnts serve as global instructive cues directing cochlear outgrowth and hair cell polarization, with remarkable redundancy of distinct Wnts across epithelial and mesenchymal compartments to ensure a fail-safe developmental program.

Morphogens cooperate to guide development of the inner ear cochlea, but how do compartments communicate? A recent study in PLOS Biology reveals how planar cell polarity of individual cells is integrated across distinct regional compartments to ensure proper organ morphogenesis.