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Influence of supporting cells on neuronal degeneration after hair cell loss.

ABSTRACT: In sensorineural hearing loss, hair cell loss is often followed by loss of cochlear nerve fibers, which can continue for years after the insult. The degree and time course of neuronal loss varies, but the reasons for this variation are unclear. The present study addresses this issue with a quantitative analysis of hair cell, supporting cell, and neuronal survival in animals with long-term survival of up to 5.5 years from two types of drug-induced hair cell loss: aminoglycoside antibiotics and platinum-containing chemotherapeutics. To complement the analysis of the effects of organ of Corti damage on neuronal survival, cases of primary neuronal degeneration, via auditory nerve section, are also assessed. Analysis shows that (1) long-term neuronal survival is enhanced when supporting cells in the inner hair cell (IHC) area remain intact; (2) after hair cell loss, the time course of neuronal loss is slower in the apex than in the base; (3) primary loss of cochlear nerve fibers does not lead to secondary degeneration of sensory cells or supporting cells in the organ of Corti; and (4) after auditory nerve section, there can be a massive reinnervation of the IHC region, especially in the apex. Results are consistent with the idea that supporting cells participate in the regulation of neuronal survival and neuronal sprouting in the organ of Corti.

SUBMITTER: Sugawara M

PROVIDER: S-EPMC2538335 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Project description:During embryonic development, differentiation of cochlear progenitor cells into hair cells (HCs) or supporting cells (SCs) is partially controlled through Notch signaling. Many studies have shown that inhibition of Notch signaling allows SCs to convert into HCs in both normal and drug damaged neonatal mouse cochleae. This mechanism is also implicated during HC regeneration in non-mammalian vertebrates; however, the mechanism of spontaneous HC regeneration in the neonatal mouse cochlea is less understood. While inhibition of Notch signaling can force SCs to convert into HCs and increase the number of regenerated HCs, it is currently unknown whether this pathway is involved in spontaneous HC regeneration observed in vivo. Therefore, we investigated the role of Notch signaling during the spontaneous HC regeneration process using Atoh1-CreERTM::Rosa26loxP-stop-loxP-DTA/+ mice injected with tamoxifen at postnatal day (P) 0 and P1 to ablate HCs and stimulate spontaneous HC regeneration. Expression changes of genes in the Notch pathway were measured using immunostaining and in situ hybridization, with most changes observed in the apical one-third of the cochlea where the majority of HC regeneration occurs. Expression of the Notch target genes Hes1, Hes5, Hey1, HeyL, and Jagged1 were decreased. To investigate whether reduction of Notch signaling is involved in the spontaneous HC regeneration process, we overexpressed the Notch1 intracellular fragment (N1ICD) in cochlear SCs and other non-sensory epithelial cells in the context of HC damage. Specifically, Atoh1-CreERTM::Rosa26loxP-stop-loxP-DTA/+::Sox10rtTA::TetO-LacZ::TetO-N1ICD mice were injected with tamoxifen at P0/P1 to stimulate spontaneous HC regeneration and given doxycycline from P0-P7 to induce expression of N1ICD as well as LacZ for fate-mapping. We observed a 92% reduction in the number of fate-mapped regenerated HCs in mice with N1ICD overexpression compared to controls with HC damage but no manipulation of Notch signaling. Therefore, we conclude that increased Notch signaling prevents spontaneous HC regeneration from occurring in the neonatal mouse cochlea. Understanding which components of the Notch pathway regulates regenerative plasticity in the neonatal mouse cochlea will inform investigations focused on stimulating HC regeneration in mature cochlea and eventually in humans to treat hearing loss.

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Influence of supporting cells on neuronal degeneration after hair cell loss.

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