Transforming growth factor‐α‐induced cellular changes in organotypic cultures of juvenile, amikacin‐treated rat organ of corti

Abstract

Hair cell losses in the mammalian cochlea following an ototoxic insult are irreversible. However, past studies have shown that amikacin treatment in rat cochleae resulted in the transient presence of atypical Deiters' cells (ACs) in the damaged organ of Corti. These ACs arise through a transformation of Deiters' cells, which produce, at their apical pole, densely packed microvilli reminiscent of early-differentiating stereociliary bundles. The ACs do not, however, express typical hair cell markers such as parvalbumin or calbindin. The present study was designed to determine whether specific growth factors could influence the survival and differentiation of these ACs and stimulate hair cell regeneration processes in vitro. Apical-medial segments of organ of Corti of juvenile amikacin-treated rats were established as organotypic cultures, and the effects of epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), transforming growth factor-alpha (TGFalpha), and retinoic acid were studied using morphological and molecular approaches. Our results indicate that TGFalpha supports the survival of the damaged organ of Corti and influences ACs differentiation in vitro, possibly acting through reorganization of the actin cytoskeleton. These effects could be directly mediated through activation of the EGF receptor, which is expressed by supporting cells in the mature organ of Corti. TGFalpha does not, however, allow the ACs to progress towards a hair cell phenotype.

EGFR signaling is required for regenerative proliferation in the cochlea: Conservation in birds and mammals

“…In light of our findings, it is interesting that adding EGF to organotypic cultures of the rodent organ of Corti has no effect on supporting cell division (Daudet et al, 2002; Romand and Chardin, 1999). The structural integrity of the claudin-rich tight junctions that characterize the apical surface of the organ of Corti may prevent polypeptides from interacting with receptors like EGFR, that are present on the lateral walls of sensory cells (cf.…”

“…Perinatal supporting cells from mouse, rat, and guinea pig retain a latent capacity to divide and differentiate into both hair cells and supporting cells in vitro (Diensthuber et al, 2009; Li et al, 2005; Lou et al, 2007; Oiticica et al, 2010; Savary et al, 2007; White et al, 2006; Zhai et al, 2005). EGF family ligands EGF and TGFα appear to promote proliferation and/or maintain progenitors under these conditions (Doetzlhofer et al, 2004; Oiticica et al, 2010), even though TGFα cannot stimulate supporting cell proliferation in the neonatal cochlea after hair cell loss (Daudet et al, 2002). How and whether these pathways connect to known intracellular regulators of proliferation, such as p27 Kip1 (Chen and Segil, 1999; Lowenheim et al, 1999) or Rb1 (Yu et al, 2010), is also unknown.…”

Expression of Prox1 defines regions of the avian otocyst that give rise to sensory or neural cells

“…In contrast, Pros expression is activated by pathways downstream of the epidermal growth factor (EGF) receptor, DER (Kauffmann et al1996;Xu et al, 2000). EGF has been implicated in promoting sensory cell production in sensory epithelia of the vertebrate inner ear (e.g., Yamashita and Oesterle, 1995;Kopke et al, 2001;Daudet et al, 2002). We demonstrate here that cProx1 is expressed in specific domains of the developing chicken otocyst that correspond to future sites of neurogenesis and hair cell formation.…”

Inner ear supporting cells: Rethinking the silent majority

“…By contrast, supporting cells divide in response to c-Myc misexpression, and some post-mitotic cells survive for long periods and differentiate hair cell features. It is likely that similar and perhaps more potent brakes on cell division are in place in the adult organ of Corti, where mitogens have limited or no impact on supporting cell quiescence (e.g., [167]).…”