Math1, retinoic acid, and TNF-α synergistically promote the differentiation of mucous cells in mouse middle ear epithelial cells in vitro

Abstract

BackgroundA key issue in otitis media (OM) is mucous cell metaplasia in the middle ear mucosa, a condition for hyperproduction of mucus in the middle ear mucosa and development of chronic OM. However, little is known about the driving force for the differentiation of mucous cells in OM.MethodsMouse middle ear epithelial cells (mMEEC) were used in this study to test whether Math1, a critical transcription factor for the development of mucous cells in the intestine, synergize with inflammatory cytokines (tumor necrotic factor alpha, TNFα) and other epithelial differentiation factors (retinoid acid, RA) to induce the differentiation of mMEEC into mucus-like cells in vitro. Simultaneously, Math1 was transduced into the middle ear mucosa and see whether it induces mucous cell hyperplasia in vivo.ResultsMath1 significantly increased the mucus cell numbers in the middle ear mucosa of mice. Math1, in the presence of TNFα and epithelial differentiation factor retinoic acid (RA), synergistically promoted the differentiation of mMEEC into mucus-like cells via upregulation of mucins and their chaperones:trefoil factors (TFFs) in vitro. RA treatment for 12 hours activated Math1 although RA alone had very limited effects on mucus-like cell differentiation.ConclusionMath1 plays a critical role in the pathogenesis of OM by induction of mucous cell differentiation, in the presence of TNFα and RA.