AAV-regulated Serpine2 overexpression promotes hair cell regeneration.

IF 6.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy. Nucleic Acids Pub Date : 2024-11-17 eCollection Date: 2024-12-10 DOI:10.1016/j.omtn.2024.102396

Qiuhan Sun, Fangzhi Tan, Xinlin Wang, Xingliang Gu, Xin Chen, Yicheng Lu, Nianci Li, Xiaoyun Qian, Yinyi Zhou, Ziyu Zhang, Man Wang, Liyan Zhang, Busheng Tong, Jieyu Qi, Renjie Chai

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Abstract

Inner ear hair cell (HC) damage is irreversible in mammals, but it has been shown that supporting cells (SCs) have the potential to differentiate into HCs. Serpine2, a serine protease inhibitor, encodes protease nexin 1, and this has been suggested to be a factor that promotes HC regeneration. In this study, we overexpressed Serpine2 in inner ear SCs cultured in two- and three-dimensional systems using the adeno-associated virus-inner ear (AAV-ie) vector, which promoted organoid expansion and HC differentiation. Overexpression of Serpine2 in the mouse cochlea through the round window membrane (RWM) injection promoted SC proliferation and HC regeneration, and the regenerated HCs were found to be derived from Lgr5⁺ SCs. Regenerated HCs have electrophysiological properties that are similar to those of native HCs. Notably, Serpine2 overexpression promoted HC survival and restored hearing of neomycin-damaged mice. In conclusion, our findings indicate that Serpine2 overexpression promotes HC regeneration and suggests that the utilization of inner ear progenitor cells in combination with AAVs might be a promising therapeutic target for hearing restoration.

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aav调节Serpine2过表达促进毛细胞再生。

哺乳动物的内耳毛细胞（HC）损伤是不可逆的，但有研究表明，支持细胞（SC）有分化为 HC 的潜力。丝氨酸蛋白酶抑制剂 Serpine2 编码蛋白酶 nexin 1，这被认为是促进 HC 再生的一个因素。在本研究中，我们使用腺相关病毒-内耳（AAV-ie）载体在二维和三维系统培养的内耳SC中过表达Serpine2，这促进了器官样组织的扩张和HC的分化。通过圆窗膜（RWM）注射在小鼠耳蜗中过表达Serpine2促进了SC增殖和HC再生，并发现再生的HC来自Lgr5+ SCs。再生的HC具有与原生HC相似的电生理特性。值得注意的是，Serpine2 的过表达促进了 HC 的存活并恢复了新霉素损伤小鼠的听力。总之，我们的研究结果表明，Serpine2 的过表达可促进 HC 的再生，并表明利用内耳祖细胞与 AAVs 结合可能是一种很有前景的听力恢复治疗靶点。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.