Hair cell stereociliary bundle regeneration by espin gene transduction after aminoglycoside damage and hair cell induction by Notch inhibition

Abstract

Once inner ear hair cells (HCs) are damaged by drugs, noise or aging, their apical structures including the stereociliary arrays are frequently the first cellular feature to be lost. While this can be followed by progressive loss of HC somata, a significant number of HC bodies often remain even after stereociliary loss. However, in the absence of stereocilia they are nonfunctional. HCs can sometimes be regenerated by Atoh1 transduction or Notch inhibition, but they also may lack stereociliary bundles. It is therefore important to develop methods for the regeneration of stereocilia, in order to achieve HC functional recovery. Espin is an actin bundling protein known to participate in sterociliary elongation during development. We evaluated stereociliary array regeneration in damaged vestibular sensory epithelia in tissue culture, using viral vector transduction of two espin isoforms. Utricular HCs were damaged with aminoglycosides. The utricles were then treated with a γ-secretase inhibitor, followed by espin or control transduction and histochemistry. While γ-secretase inhibition increased the number of HCs, few had stereociliary arrays. In contrast, 46 hrs after espin1 transduction, a significant increase in hair-bundle-like structures was observed. These were confirmed to be immature stereociliary arrays by scanning electron microscopy. Increased uptake of FM1–43 uptake provided evidence of stereociliary function. Espin4 transduction had no effect. The results demonstrate that espin1 gene therapy can restore stereocilia on damaged or regenerated HCs.

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

“…Multiple genes in addition to those identified here will most likely need to be manipulated. For example, ectopic espin1, concomitant to p27 and ATOH1 or hPOU4F3 and ATOH1 manipulations, may be useful in promoting normal bundle morphology (Taura et al, 2016). Also, the enhancement of Wnt/β-catenin signaling in addition to the manipulations described above could increase the numbers of cells that convert to HCs (Kuo et al, 2015; Ni et al, 2016).…”

Gene, cell, and organ multiplication drives inner ear evolution

“…When and how factors that coordinate polarity of hair cells across sensory epithelia (May-Simera et al, 2015) evolved is unclear. Thus, while some connections between Atoh1 level of expression and some of the downstream factors needed for the apical development of the stereocilia bundle are likely (Taura et al, 2016), we do not yet understand how vestibular and cochlear hair cells molecularly evolved their unique stereocilia organization and loss of a kinocilium. Atoh1 and other factors are also expressed in and needed for Merkel cell development (Bermingham et al, 2001) and Merkel cells share a mechanotransduction channel [Piezo2 (Woo et al, 2014)] with some hair cells (Wu et al, 2016) indicating the possibility that this highly conserved channel is directly tied into Atoh1 signaling, possibly derived from an ancestral function in epidermal cells (Arendt et al, 2016).…”

A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer’s-like pathology

“…Natural products and their derivatives such as glycosides are emerging drug candidates for AD therapy owing to their diverse biological functions under pathological circumstances [20, [24][25][26]. Among various pharmacological properties, the glycosides exhibit antioxidative and anti-inflammatory activities in diabetes, cardiovascular disease, and AD [19,27].…”