TRIM71 reactivation enhances the mitotic and hair cell-forming potential of cochlear supporting cells

• Published in: EMBO reports Vol. 24; no. 9; p. e56562
• Main Authors: Li, Xiao-Jun, Morgan, Charles, Nadar-Ponniah, Prathamesh T, Kolanus, Waldemar, Doetzlhofer, Angelika
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 06.09.2023; John Wiley and Sons Inc
• Subjects: Animals; Cell cycle; Cell differentiation; Cell Differentiation - genetics; Cell division; Cochlea; Cochlea - metabolism; Deafness; Gene Expression Profiling; Hair; Hair cells; Hair Cells, Auditory - metabolism; Hearing loss; Hearing protection; Humans; Mice; Mitosis; Organoids; Progenitor cells; Regenerative medicine; Ribonucleic acid; RNA; RNA-binding protein; Stem cells; Stem Cells - metabolism; Transcriptomics; Tripartite Motif Proteins - genetics; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Lin28b; cochlea; Trim71; supporting cell reprogramming; hair cell regeneration
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202256562

Cochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B target Trim71 as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming; however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 re-expression increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71's RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B target Hmga2 is essential for supporting cell self-renewal and hair cell formation.