Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice.
Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice.
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DOI：
10.1073/pnas.2215253120
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发表时间：
2023-04-25
影响因子：
11.1
通讯作者：
Chen, Zheng-Yi
中科院分区：
文献类型：
--
作者：
Quan, Yi-Zhou;Wei, Wei;Ergin, Volkan;Rameshbabu, Arun Prabhu;Huang, Mingqian;Tian, Chunjie;Saladi, Srinivas Vinod;Indzhykulian, Artur A.;Chen, Zheng-Yi
听力损失影响着数百万人，没有一种fda批准的治疗药物。内耳感觉细胞，即毛细胞的丧失，被认为是导致听力损失的最常见原因之一，通常是永久性的。这种损失不能由终末分化的支持细胞来补偿，这些支持细胞不容易在成年小鼠耳蜗中转分化为新的毛细胞。Quan等人利用单细胞RNAseq、高级成像、电生理学和谱系追踪，发现了一种由小分子和sirna组成的药物样分子的组合（鸡尾酒），有效地重编程了毛细胞缺失小鼠模型中完全成熟的野生型支持细胞，用于毛细胞样细胞再生，代表了HC再生听力恢复的一步。克服哺乳动物耳蜗毛细胞（HC）不可逆损伤和损失的策略对永久性听力损失患者的听力恢复至关重要。在成熟的哺乳动物耳蜗中，Myc和Notch1的共同激活可重编程支持细胞（SC）并促进HC再生。了解其潜在机制可能有助于开发一种临床相关的方法来实现非转基因成熟耳蜗的HC再生。通过单细胞RNAseq，我们发现MYC/NICD通过激活包括Wnt和环化酶激活剂环化AMP （cAMP）在内的多种途径来“恢复”成年小鼠耳蜗，尽管MYC/ Notch被激活，但cAMP的阻断抑制了hc样细胞的再生。我们筛选并鉴定了由小分子和小干扰rna组成的药物样分子的组合（鸡尾酒），以激活Myc， Notch1， Wnt和cAMP的通路。我们发现这种混合物有效地取代了Myc和Notch1转基因，并对完全成熟的野生型（WT） SCs进行了重编程，使其在体外再生hc样细胞。最后，我们证明了这种鸡尾酒能够在体内HC缺失的WT小鼠中对成年耳蜗进行重编程，使HC样细胞再生。本研究通过临床相关的方法确定了成熟内耳HC样细胞再生的重编程策略，为HC再生听力恢复奠定了基础。
Hearing loss affects millions of people without a single FDA-approved drug for treatment. The loss of the inner ear sensory cells, the hair cells, is considered one of the most common causes of hearing loss that is generally permanent. Such loss cannot be compensated by the terminally differentiated supporting cells, which do not readily transdifferentiate into new hair cells in adult mouse cochleae. Using single-cell RNAseq, advanced imaging, electrophysiology, and lineage tracing, Quan et al. identified a combination (the cocktail) of drug-like molecules composed of small molecules and siRNAs that effectively reprograms fully mature wild-type supporting cells for hair cell-like cell regeneration in a mouse model with hair cell loss, representing a step forward for hearing restoration by HC regeneration. Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the nontransgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD “rejuvenates” the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation. We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.
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