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

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.

SUBMITTER: Dr. Xiao-Jun Li

PROVIDER: S-SCDT-10_15252-EMBR_202256562 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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.

| S-EPMC10481673 | biostudies-literature

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space.

Project description:Neurons in developing sensory pathways exhibit spontaneous bursts of electrical activity that are critical for survival, maturation and circuit refinement. In the auditory system, intrinsically generated activity arises within the cochlea, but the molecular mechanisms that initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 activation triggers K+ efflux and depolarization of hair cells, as well as osmotic shrinkage of supporting cells that dramatically increased the extracellular space and speed of K+ redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal burst firing by reducing K+ release, but unexpectedly enhanced their tonic firing, as water resorption by supporting cells reduced the extracellular space, leading to K+ accumulation. These studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by controlling the volume of the extracellular space.

| S-EPMC7015667 | biostudies-literature

Intrinsic regenerative potential of murine cochlear supporting cells

Project description:P3 Math1-nGFP mouse cochlear sensory epithelia, consisting of greater and lesser epithelial ridges (GER & LER) including the organ of Corti with nGFP-positive hair cells, were dissected, dissociated into single cells, and labeled with propidium iodide and three CD marker antibodies. The cell suspension was subjected to FACS purification. 83.6 ±2.8% of the total input of cells were viable, determined by exclusion of propidium iodide. Only viable cells were collected into 5 distinct populations: GFP+ cells (Samples HC_A-D), GFP?/CD271High (Samples Mac_A-C), as well as GFP?/CD271Low/CD326+/CD146Low (Samples SC_A-B), GFP?/CD271Low/CD326+/CD146Hig (Samples GER_A-B), and GFP?/CD271Low/CD326? (Sample BM_B). Please see Sinkkonen et al 2011 PMID: 22355545 Total RNA was isolated from 5 different FACS sorted cell poulations from P3 Math1-nGFP cochlea.

2014-10-22 | E-GEOD-62582 | biostudies-arrayexpress

Dibenzazepine promotes cochlear supporting cell proliferation and hair cell regeneration in neonatal mice.

Project description:ObjectivesTo investigate the role of dibenzazepine (DBZ) in promoting supporting cell (SC) proliferation and hair cell (HC) regeneration in the inner ear.Materials and methodsPostnatal day 1 wild-type or neomycin-damaged mouse cochleae were cultured with DBZ. Immunohistochemistry and scanning electron microscopy were used to examine the morphology of cochlear cells, and high-throughput RNA-sequencing was used to measure gene expression levels.ResultsWe found that DBZ promoted SC proliferation and HC regeneration in a dose-dependent manner in both normal and damaged cochleae. In addition, most of the newly regenerated HCs induced by DBZ had visible and relatively mature stereocilia bundle structures. Finally, RNA sequencing detected the differentially expressed genes between DBZ treatment and controls, and interaction networks were constructed for the most highly differentially expressed genes.ConclusionsOur study demonstrates that DBZ can significantly promote SC proliferation and increase the number of mitotically regenerated HCs with relatively mature stereocilia bundles in the neonatal mouse cochlea by inhibiting Notch signalling and activating Wnt signalling, suggesting the DBZ might be a new therapeutic target for stimulating HC regeneration.

| S-EPMC7507434 | biostudies-literature

Virus-infection in cochlear supporting cells induces audiosensory receptor hair cell death by TRAIL-induced necroptosis.

Project description:Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

| S-EPMC8629241 | biostudies-literature

Intrinsic regenerative potential of murine cochlear supporting cells

Project description:P3 Math1-nGFP mouse cochlear sensory epithelia, consisting of greater and lesser epithelial ridges (GER & LER) including the organ of Corti with nGFP-positive hair cells, were dissected, dissociated into single cells, and labeled with propidium iodide and three CD marker antibodies. The cell suspension was subjected to FACS purification. 83.6 ±2.8% of the total input of cells were viable, determined by exclusion of propidium iodide. Only viable cells were collected into 5 distinct populations: GFP+ cells (Samples HC_A-D), GFP−/CD271High (Samples Mac_A-C), as well as GFP−/CD271Low/CD326+/CD146Low (Samples SC_A-B), GFP−/CD271Low/CD326+/CD146Hig (Samples GER_A-B), and GFP−/CD271Low/CD326− (Sample BM_B). Please see Sinkkonen et al 2011 PMID: 22355545

2014-10-22 | GSE62582 | GEO

Cochlear supporting cells function as macrophage-like cells and protect audiosensory receptor hair cells from pathogens.

Project description:To protect the audiosensory organ from tissue damage from the immune system, the inner ear is separated from the circulating immune system by the blood-labyrinth barrier, which was previously considered an immune-privileged site. Recent studies have shown that macrophages are distributed in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis; however, the direct pathogen defence mechanism used by audiosensory receptor hair cells (HCs) has remained obscure. Here, we show that HCs are protected from pathogens by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs). In isolated murine cochlear sensory epithelium, we established Theiler's murine encephalomyelitis virus, which infected the SCs and GERCs, but very few HCs. The virus-infected SCs produced interferon (IFN)-α/β, and the viruses efficiently infected the HCs in the IFN-α/β receptor-null sensory epithelium. Interestingly, the virus-infected SCs and GERCs expressed macrophage marker proteins and were eliminated from the cell layer by cell detachment. Moreover, lipopolysaccharide induced phagocytosis of the SCs without cell detachment, and the SCs phagocytosed the bacteria. These results reveal that SCs function as macrophage-like cells, protect adjacent HCs from pathogens, and provide a novel anti-infection inner ear immune system.

| S-EPMC7174420 | biostudies-literature

Hair cell and neural contributions to the cochlear summating potential.

Project description:The cochlear summating potential (SP) to a tone is a baseline shift that persists for the duration of the burst. It is often considered the most enigmatic of cochlear potentials because its magnitude and polarity vary across frequency and level and its origins are uncertain. In this study, we used pharmacology to isolate sources of the SP originating from the gerbil cochlea. Animals either had the full complement of outer and inner hair cells (OHCs and IHCs) and an intact auditory nerve or had systemic treatment with furosemide and kanamycin (FK) to remove the outer hair cells. Responses to tone bursts were recorded from the round window before and after the neurotoxin kainic acid (KA) was applied. IHC responses were then isolated from the post-KA responses in FK animals, neural responses were isolated from the subtraction of post-KA from pre-KA responses in NH animals, and OHC responses were isolated by subtraction of post-KA responses in FK animals from post-KA responses in normal hearing (NH) animals. All three sources contributed to the SP; OHCs with a negative polarity and IHCs and the auditory nerve with positive polarity. Thus the recorded SP in NH animals is a sum of contributions from different sources, contributing to the variety of magnitudes and polarities seen across frequency and intensity. When this information was applied to observations of the SP recorded from the round window in human cochlear implant subjects, a strong neural contribution to the SP was confirmed in humans as well as gerbils. NEW & NOTEWORTHY Of the various potentials produced by the cochlea, the summating potential (SP) is typically described as the most enigmatic. Using combinations of ototoxins and neurotoxins, we show contributions to the SP from the auditory nerve and from inner and outer hair cells, which differ in polarity and vary in size across frequency and level. This complexity of sources helps to explain the enigmatic nature of the SP.

| S-EPMC6620691 | biostudies-literature

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells.

Project description:Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single-cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

| S-EPMC8439656 | biostudies-literature

Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti.

Project description:The adult mammalian cochlear sensory epithelium houses two major types of cells, mechanosensory hair cells and underlying supporting cells, and lacks regenerative capacity. Recent evidence indicates that a subset of supporting cells can spontaneously regenerate hair cells after ablation only within the first week postparturition. Here in vivo clonal analysis of mouse inner ear cells during development demonstrates clonal relationship between hair and supporting cells in sensory organs. We report the identification in mouse of a previously unknown population of multipotent stem/progenitor cells that are capable of not only contributing to the hair and supporting cells but also to other cell types, including glia, in cochlea undergoing development, maturation and repair in response to damage. These multipotent progenitors originate from Eya1-expressing otic progenitors. Our findings also provide evidence for detectable regenerative potential in the postnatal cochlea beyond 1 week of age.

| S-EPMC5437288 | biostudies-literature

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