Growth factors have a protective effect on neomycin‐induced hair cell loss

Abstract

We have demonstrated that selected growth factors are involved in regulating survival and proliferation of progenitor cells derived from the neonatal rat organ of Corti (OC). The protective and regenerative effects of these defined growth factors on the injured organ of Corti were therefore investigated. The organ of Corti dissected from the Wistar rat pups (P3-P5) was split into apical, middle, and basal parts, explanted and cultured with or without neomycin and growth factors. Insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF) protected the inner hair cells (IHCs) and outer hair cells (OHCs) from neomycin ototoxicity. Using EGF, IGF-1, and FGF-2 alone induced no protective effect on the survival of auditory hair cells. Combining 2 growth factors (EGF + IGF-1, EGF + FGF-2, or IGF-1 + FGF-2) gave statistically protective effects. Similarly, combining all three growth factors effectively protected auditory hair cells from the ototoxic insult. None of the growth factors induced regeneration of hair cells in the explants injured with neomycin. Thus various combinations of the three defined factors (IGF-1, FGF-2, and EGF) can protect the auditory hair cells from the neomycin-induced ototoxic damage, but no regeneration was seen. This offers a possible novel approach to the treatment of hearing loss.

Characterization of the Transcriptomes of Lgr5+ Hair Cell Progenitors and Lgr5- Supporting Cells in the Mouse Cochlea

“…The pathway genes that are highly expressed in Lgr5+ progenitors include Kcnh8 , Mknk1 , Shc1 , Cdon , Disp2 , Erbb4 , Hhip , Ihh , Npc1 , Dll1 , Dll3 , Dll4 , Figf , Hes5 , Mfng , Neurl1a , Notch4 , Rbpjl , Dkk1 , Fgf4 , Wnt4 , Wnt8b , Fat3 , Rassf2 , Tjp2 , Tshz2 , and Tshz3 . Among them, Axin2 (Jan et al, 2013; Jansson et al, 2015), Egf (Lou et al, 2015), Wnt4 (Alvarado et al, 2011), Tjp2 (Kim et al, 2014), Dll1 (Kiernan et al, 2005; Chrysostomou et al, 2012), and Dll3 (Hartman et al, 2007) have already been reported in the inner ear. Some of the pathway genes that are highly expressed in Lgr5- SCs include Akt1 , Atf1 , Bcl2 , Ccnd1 , Dusp6 , Egr1 , Fos , Grb2 , Jun , Kras , Lta , Pik3r1 , Pik3r2 , Plat , Ppp2ca , Rhoa , Dhh , Fgf9 , Fkbp8 , Kctd11 , Prkacb , Ptch1 , Stk3 , Fos , Hesl , Heyl , Krt1 , Ncstn , Psen1 , Ccnd2, Dkk3, Fzd8, Fzd9, Fkbp8, Jun, Nkd1, Rhou , Wif1 , Frzb , Wnt5a, Wnt6 , Ajuba , Amotl2 , Csnk1d , Hipk2 , Mob1a , Pard6g , Stk3 , Wisp1 , Taz , Tead1 , and Wwc1 .…”

“…Axin2 acts as a Wnt target gene, and its expression in tympanic border cells allows them to behave as HC progenitors (Jan et al, 2013; Jansson et al, 2015). Combined with other growth factors, Egf can protect HCs from ototoxic damage (Lou et al, 2015). Wnt4 is detected in the inner and outer spiral sulcus cells, as well as in the Claudius and Hensen’s cells, and downregulation of Wnt4 expression significantly reduces the proliferation of SCs (Alvarado et al, 2011).…”

Protein Synthesis Inhibition and Activation of the c-Jun N-Terminal Kinase Are Potential Contributors to Cisplatin Ototoxicity

“…The otoprotective effect of insulin, for example, might be mediated by mechanisms independent from protein synthesis stimulation. Several previous reports have described that growth factors such as IGF-1, EGF, TGF alpha and insulin protect against various ototoxic insults (Romand and Chardin, 1999 ; Iwai et al, 2006 ; Lou et al, 2015 ; Yamahara et al, 2015 ). In the case of IGF-1, protection was mediated by supporting cells (Yamahara et al, 2015 ).…”

Activation of PI3K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea

“…Activation of PI3K signaling by binding of soluble ligands or chemokines to receptor tyrosine kinases ( Chalhoub and Baker, 2009 ) could be responsible for promoting hair cell survival. Ligands such as insulin-like growth factor (IGF) 1 and IGF2 were reported to maintain hair cell survival ( Lou et al, 2015 ; Malgrange et al, 2002 ). Mice harboring inactive IGF1 receptors (IGF1R) showed profound sensorineural hearing loss and a delay in hair cell development ( Okano et al, 2011 ).…”