Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds

Abstract

Debilitating hearing and balance deficits often arise through damage to the inner ear's hair cells. For humans and other mammals, such deficits are permanent, but non-mammalian vertebrates can quickly recover hearing and balance through their innate capacity to regenerate hair cells. The biological basis for this difference has remained unknown, but recent investigations in wounded balance epithelia have shown that proliferation follows cellular spreading at sites of injury. As mammalian ears mature during the first weeks after birth, the capacity for spreading and proliferation declines sharply. In seeking the basis for those declines, we investigated the circumferential bands of F-actin that bracket the apical junctions between supporting cells in the gravity-sensitive utricle. We found that those bands grow much thicker as mice and humans mature postnatally, while their counterparts in chickens remain thin from hatching through adulthood. When we cultured utricular epithelia from chickens, we found that cellular spreading and proliferation both continued at high levels, even in the epithelia from adults. In contrast, the substantial reinforcement of the circumferential F-actin bands in mammals coincides with the steep declines in cell spreading and production established in earlier experiments. We propose that the presence of thin F-actin bands at the junctions between avian supporting cells may contribute to the lifelong persistence of their capacity for shape change, cell proliferation, and hair cell replacement, while the postnatal reinforcement of the F-actin bands in maturing humans and other mammals may have an important role in limiting hair cell regeneration.

Cytoskeletal changes in actin and microtubules underlie the developing surface mechanical properties of sensory and supporting cells in the mouse cochlea

“…By examining downstream inhibitors of this signaling cascade, we provide insights that link this pathway to actin dynamics via ROCK, which might account, at least in part, for the observed rescue of cell stiffness. Furthermore, recent work in the developing vestibular epithelium has suggested a possible role for increased actin in the inhibition of hair cell regeneration (Burns et al, 2008). Results presented here suggest that treatment with Fgfs, which act to prevent actin polymerization in hair cells, could be considered as a potential intervention in actin-belt formation in supporting cells, and as a key component to consider when trying to repair damaged epithelia.…”

Over Half the Hair Cells in the Mouse Utricle First Appear After Birth, with Significant Numbers Originating from Early Postnatal Mitotic Production in Peripheral and Striolar Growth Zones

“…We have described circumferential F-actin belts at the apical junctions of supporting cells in the vestibular epithelia of mice and humans that become reinforced as mammals mature postnatally, while their counterparts in birds remain thin throughout life (Burns et al 2008). The growth of the belts in rodents correlates inversely with a progressive decrease in the incidence of supporting cell proliferation in cultured explants of the vestibular epithelia from postnatal rodents (r0−0.98).…”

“…Balance organs from non-mammals produce new hair cells and supporting cells in vivo. In culture, cells within those sensory epithelia show even more robust spreading and proliferation that remain undiminished from birth to adulthood (Burns et al 2008), and they exhibit considerable regenerative capacities throughout life. In a separate article, we report that the utricles of mice that are beyond the age when proliferation occurs during normal postnatal growth of the macula retain the capacity for regenerating hair cells in vivo.…”

Changes in the adult vertebrate auditory sensory epithelium after trauma

“…Support cells in the mammalian organ of Corti are highly specialized in contrast to support cells in non-mammalian auditory epithelia, and it is possible that as a consequence of their specialization, they have lost the ability to divide or transdifferentiate following hair cell loss. It has been hypothesized that support cell proliferative ability is lost because of the absence of certain mitogenic receptors and signaling pathways, the expression of cell cycle inhibitors such as p27 Kip1 , the lack of expression of cell cycle-positive regulators such as cyclin D1, the expression of additional inhibitory signaling pathways, and/or changes in the actin cytoskeleton (e.g., White et al, 2006; Burns et al, 2008; Laine et al, 2010; McCullar et al, 2010; Oesterle et al, 2011; Liu et al, 2012c). It has been shown that pluripotent stem cells, present in regenerating organs such as intestine and skin, appear to be absent in the mature cochlea.…”