PDF(Pubmed)
Abstract：
In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters\' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.
摘要：
在哺乳动物中,由于听觉上皮缺乏再生能力，听力损失是不可逆的。然而,哺乳动物耳蜗中的干/祖细胞可能是听力再生的治疗靶标。泛素蛋白酶体系统在耳蜗发育和维持中起着重要作用。在这项研究中,我们研究了泛素C末端水解酶L1(UCHL1)在听觉支持细胞(SC)向毛细胞(HC)转分化过程中的作用.随着HC的发展，UCHL1的表达逐渐降低，并且仅限于内柱细胞和P2和P7之间的第三行Deiters'细胞，这表明表达UCHL1的细胞与具有Lgr5阳性祖细胞的细胞相似。即使在用γ-分泌酶抑制剂和Wnt激动剂产生过量HC的条件下,UCHL1表达也降低。此外，LDN-57444对UCHL1的抑制作用导致HC数量增加。机械上,LDN-57444增加mTOR复合物1活性并允许SC转分化为HC。抑制UCHL1通过调节mTOR通路诱导听觉SCs和祖细胞转分化为HC。
