Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California, USA.
Department of Otology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
J Clin Invest. 2018 Apr 2;128(4):1641-1656. doi: 10.1172/JCI97248. Epub 2018 Mar 19.
During development, Sox2 is indispensable for cell division and differentiation, yet its roles in regenerating tissues are less clear. Here, we used combinations of transgenic mouse models to reveal that Sox2 haploinsufficiency (Sox2haplo) increases rather than impairs cochlear regeneration in vivo. Sox2haplo cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2haplo amplified and expanded domains of damage-induced Atoh1+ transitional cell formation in neonatal cochlea. Wnt activation via β-catenin stabilization (β-cateninGOF) alone failed to induce proliferation or transitional cell formation. By contrast, β-cateninGOF caused proliferation when either Sox2haplo or damage was present, and transitional cell formation when both were present in neonatal, but not mature, cochlea. Mechanistically, Sox2haplo or damaged neonatal cochleae showed lower levels of Sox2 and Hes5, but not of Wnt target genes. Together, our study unveils an interplay between Sox2 and damage in directing tissue regeneration and Wnt responsiveness and thus provides a foundation for potential combinatorial therapies aimed at stimulating mammalian cochlear regeneration to reverse hearing loss in humans.
在发育过程中，Sox2 对于细胞分裂和分化是不可或缺的，但它在组织再生中的作用尚不清楚。在这里，我们使用了转基因小鼠模型的组合，揭示了 Sox2 杂合不足（Sox2haplo）增加而不是损害体内耳蜗再生。Sox2haplo 耳蜗有延迟的终末有丝分裂和异位感觉细胞，但听觉功能正常。Sox2haplo 扩增和扩大了损伤诱导的 Atoh1+过渡细胞形成的区域在新生耳蜗。通过β-连环蛋白稳定化（β-cateninGOF）单独激活 Wnt （β-cateninGOF）不足以诱导增殖或过渡细胞形成。相比之下，β-cateninGOF 在存在 Sox2haplo 或损伤的情况下引起增殖，并且在新生但不是成熟的耳蜗中，当两者都存在时，过渡细胞形成。从机制上讲，Sox2haplo 或受损的新生耳蜗表现出较低水平的 Sox2 和 Hes5，但不是 Wnt 靶基因。总之，我们的研究揭示了 Sox2 和损伤在指导组织再生和 Wnt 反应性方面的相互作用，为旨在刺激哺乳动物耳蜗再生以逆转人类听力损失的潜在组合疗法提供了基础。
