Ren Hongmiao, Guo Weiwei, Liu Wei, Gao Weiqiang, Xie Dinghua, Yin Tuanfang, Yang Shiming, Ren Jihao
Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University Guangzhou 510080, Guangdong, P.R. China.
Department of Otolaryngology Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital Beijing, China.
Am J Transl Res. 2016 Feb 15;8(2):634-43. eCollection 2016.
Hearing loss is currently an incurable degenerative disease characterized by a paucity of hair cells (HCs), which cannot be spontaneously replaced in mammals. Recent technological advancements in gene therapy and local drug delivery have shed new light for hearing loss. Atoh1, also known as Math1, Hath1, and Cath1, is a proneural basic helix-loop-helix (bHLH) transcription factor that is essential for HC differentiation. At various stages in development, Atoh1 activity is sufficient to drive HC differentiation in the cochlea. Thus, Atoh1 related gene therapy is the most promising option for HC induction. DAPT, an inhibitor of Notch signaling, enhances the expression of Atoh1 indirectly, which in turn promotes the induction of a HC fate. Here, we show that DAPT cooperates with Atoh1 to synergistically promote HC fate in ependymal cells in vitro and promote hair cell regeneration in the cultured basilar membrane (BM) which mimics the microenvironment in vivo. Taken together, our findings demonstrated that DAPT is sufficient to induce HC-like cells via enhancing of the expression of Atoh1 to inhibit the progression of HC apoptosis and to induce new HC formation.
听力损失目前是一种无法治愈的退行性疾病，其特征是毛细胞（HCs）数量稀少，而在哺乳动物中毛细胞无法自发替代。基因治疗和局部药物递送方面的最新技术进展为听力损失带来了新的曙光。Atoh1，也被称为Math1、Hath1和Cath1，是一种神经前体碱性螺旋-环-螺旋（bHLH）转录因子，对毛细胞分化至关重要。在发育的各个阶段，Atoh1的活性足以驱动耳蜗中的毛细胞分化。因此，与Atoh1相关的基因治疗是诱导毛细胞最有前景的选择。DAPT是一种Notch信号通路抑制剂，它间接增强Atoh1的表达，进而促进毛细胞命运的诱导。在此，我们表明DAPT与Atoh1协同作用，在体外的室管膜细胞中协同促进毛细胞命运，并在模拟体内微环境的培养基底膜（BM）中促进毛细胞再生。综上所述，我们的研究结果表明，DAPT通过增强Atoh1的表达来诱导类似毛细胞的细胞，从而抑制毛细胞凋亡的进程并诱导新的毛细胞形成。
