TRIM71 reactivation enhances the mitotic and hair cell–forming potential of cochlear supporting cells
Xiaojun Lia b, Charles Morgana b, Prathamesh T. Nadar‐Ponniaha b, Waldemar Kolanusc d e, Angelika Doetzlhofera b f g✉
- aThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- bThe Solomon H. Snyder Department of Neuroscience Johns Hopkins University School of Medicine Baltimore MD USA
- cMolecular Immunology and Cell Biology, Life & Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
- dMolecular Immunology and Cell Biology, Life &
- eMedical Sciences Institute (LIMES) University of Bonn Bonn Germany
- fDepartment of Otolaryngology and Center for Hearing and Balance, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- gDepartment of Otolaryngology and Center for Hearing and Balance Johns Hopkins University School of Medicine Baltimore MD USA
- ✉Corresponding author
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Abstract
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.