Variations in Shape-Sensitive Restriction Points Mirror Differences in the Regeneration Capacities of Avian and Mammalian Ears

Abstract

When inner ear hair cells die, humans and other mammals experience permanent hearing and balance deficits, but non-mammalian vertebrates quickly recover these senses after epithelial supporting cells give rise to replacement hair cells. A postnatal decline in cellular plasticity appears to limit regeneration in mammalian balance organs, where declining proliferation responses are correlated with decreased spreading of supporting cells on artificial and native substrates. By culturing balance epithelia on substrates that differed in flexibility, we assessed spreading effects independent of age, showing a strong correlation between shape change and supporting cell proliferation. Then we made excision wounds in utricles cultured from young and old chickens and mice and compared quantified levels of spreading and proliferation. In utricles from young mice, and both young and old chickens, wounds re-epithelialized in <24 hours, while those in utricles from mature mice took three times longer. More cells changed shape in the fastest healing wounds, which accounted for some differences in the levels of proliferation, but inter-species and age-related differences in shape-sensitive restriction points, i.e., the cellular thresholds for shape changes that promote S-phase, were evident and may be particularly influential in the responses to hair cell losses in vivo.

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

“…This is a slower time course of engulfment and removal than was described in the chick 15 and it is consistent with observations regarding the enhanced responsiveness of chick versus mammalian SCs during wound healing. 38 We also observed instances in which SCs ultimately push the HC corpse deeper into the epithelium, consistent with the idea that macrophages may also participate in the late stages of removal of dead HCs. 39 SCs generally advanced toward the apex of the HC concurrently with or following HC death.…”

In VivoProliferative Regeneration of Balance Hair Cells in Newborn Mice

“…The results here are consistent with the hypothesis that rapid neonatal maturation of uniquely specialized intercellular junctions contributes to restricting the plasticity that immature mammalian supporting cells appear to exhibit, since those junctions change markedly between P0 and P4 (Burns et al, 2008; Collado et al, 2011a); but causality has not been established. This and alternative hypotheses now may be more readily tested, since the findings here show that when pre-existing hair cells are killed at an early stage of neonatal life, mice can mitotically regenerate significant numbers of hair cells in vivo .…”

“…Instead, the decline in proliferative response mirrors an age-related decline in the propensity for rodent supporting cells to change from columnar to spread shapes both in cultured sheets and vestibular epithelia healing in situ (Davies et al, 2007; Meyers and Corwin, 2007). Contrasting with this, supporting cells in utricular epithelia from adult birds continue to exhibit rapid spreading and high rates of proliferation that are undiminished from those of hatchlings (Burns et al, 2008; Collado et al, 2011a). …”

Inner ear supporting cells: Rethinking the silent majority

“…Consistent with this, the capacity for colony formation amongst inner ear supporting cells upon dissociation progressively decreases over the postnatal period [181]. Another idea recently put forth is that the apical cytoskeleton of mammalian supporting cells becomes more restrictive to cell spreading upon hair cell loss and thus prevents them from dividing or transdifferentiating [182, 183]. Another confounding factor is the more dramatic restriction of mammalian auditory supporting cells that occurs after hair cell loss, which is evident in both their morphology and proliferative potential [184, 185].…”