Targeted deletion of Atoh8 results in severe hearing loss in mice.

Atoh8, also named Math6, is a bHLH gene reported to have important functions in the developing nervous system, pancreas and kidney. However, the expression pattern and function of Atoh8 in the inner ear are still unclear. To study the function of Atoh8 in the developing mouse inner ear, we performed targeted deletion of Atoh8 by intercrossing Atoh8lacZ/+ mice. We studied the expression pattern of Atoh8 in the inner ear and found interesting results that Atoh8-null (Atoh8lacZ/lacZ ) mice were viable but smaller than their littermates and they were severely hearing impaired, which was confirmed by hearing tests (ABR, DPOAE). We collected 129 viable newborns from 18 litters by crossing Atoh8lacZ/+ mice and found that the distributions of Atoh8lacZ/+ , Atoh8lacZ/lacZ and wild type were very close to their expected Mendelian ratio by χ2 testing. However, no remarkable morphological changes in cochleae in mutant mice were detected under plastic sectioning and electron microscopy. No remarkable differences in the expression of Myosin6, Prestin, TrkC, GAD65, Tuj1, or Calretinin were detected between the mutant mice and the control mice. These findings indicate that Atoh8 plays an important role in the development of normal hearing, while further studies are required to elucidate its exact function in hearing.

Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells.

The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging. ATOH1 is a key gene in the development and regeneration of hair cells. Small activating RNAs (saRNAs) can target a gene to specifically upregulate its expression. This study aimed to explore whether small activating RNAs could induce the differentiation of human adipose-derived mesenchymal stem cells into hair cell-like cells with a combination of growth factors in vitro and thus provide a new strategy for hair cell regeneration and the treatment of sensorineural hearing loss. Fifteen small activating RNAs targeting the human ATOH1 gene were designed and screened in 293 T and human adipose-derived mesenchymal stem cells, and 3 of these candidates were found to be capable of effectively and stably activating ATOH1 gene expression. The selected small activating RNAs were then transfected into hair cell progenitor cells, and hair cell markers were examined 10 days after transfection. After transfection of the selected small activating RNAs, the expression of the characteristic markers of inner ear hair cells, POU class 4 homeobox 3 (POU4F3) and myosin VIIA (MYO7A), was detected. Human adipose-derived mesenchymal stem cells have the potential to differentiate into human hair cell progenitor cells. In vitro, small activating RNAs were able to induce the differentiation of hair cell progenitor cells into hair cell-like cells. Therefore, RNA activation technology has the potential to provide a new strategy for the regeneration of hair cells.

Predictors of anatomical and functional outcomes following tympanoplasty: A retrospective study of 413 procedures.

OBJECTIVES: To identify the predictors of anatomical and functional outcomes following tympanoplasty. STUDY DESIGN: A retrospective cohort study. METHODS: Patients with chronic suppurative otitis media (CSOM) who underwent a tympanoplasty at Peking Union Medical College Hospital from January 1, 2015 to December 31, 2019 were retrospectively included. Outcome measures included graft success and postoperative pure tone audiometry air-bone gap (PTA-ABG) at last follow-up (≥6 months). PTA-ABG and MERI were calculated. Descriptive, univariable, and multivariable logistic regression analyses were conducted to evaluate the predictors of the graft and hearing outcomes. RESULTS: During the study, 385 patients (167 male, 218 female, median age 44 years) undergoing 413 procedures were studied. Out of this, 219 ears underwent tympanoplasty, 45 ears had tympanoplasty with canal wall up mastoidectomy, and 149 ears had tympanoplasty with canal wall down mastoidectomy. At the last follow-up, the overall graft success rate was 91.3% (377/413) and the overall hearing success rate was 40% (165/413). Multivariable analysis results showed that the obstructed aditus ad antrum (OR 2.67, 95%CI 1.13-6.30; P = .025) was an independent prognostic factor for graft failures. Moreover, the obstructed aditus ad antrum (OR 2.18, 95%CI 1.16-4.08; P = .015) and MERI >3 (OR 6.53, 95%CI 3.55-12.02; P < .001) were independent predictors of hearing failures (PTA-ABG > 20 dB). CONCLUSIONS: Aditus ad antrum patency was an independent predictor of both graft and hearing success among patients following tympanoplasty. MERI score greater than three was found to be a significant predictor of postoperative hearing and could serve as a useful tool for assisting clinicians in perioperative risk assessment. LEVEL OF EVIDENCE: 4.