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

Abstract

AbstractCochlear 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.