AAV-mediated Gene Cocktails Enhance Supporting Cell Reprogramming and Hair Cell Regeneration.

Autor: Zhang L; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Chen X; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Wang X; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Zhou Y; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Fang Y; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Gu X; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Zhang Z; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Sun Q; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Li N; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Xu L; Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250022, China.; Shandong Institute of Otorhinolaryngology, Jinan, 250022, China., Tan F; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China., Chai R; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.; Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.; Department of Otolaryngology-Head and Neck Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.; Southeast University Shenzhen Research Institute, Shenzhen, 518063, China., Qi J; State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.; Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Aug; Vol. 11 (29), pp. e2304551. Date of Electronic Publication: 2024 May 29.
DOI: 10.1002/advs.202304551
Abstrakt: Mammalian cochlear hair cells (HCs) are essential for hearing, and damage to HCs results in severe hearing impairment. Damaged HCs can be regenerated by neighboring supporting cells (SCs), thus the functional regeneration of HCs is the main goal for the restoration of auditory function in vivo. Here, cochlear SC trans-differentiation into outer and inner HC by the induced expression of the key transcription factors Atoh1 and its co-regulators Gfi1, Pou4f3, and Six1 (GPAS), which are necessary for SCs that are destined for HC development and maturation via the AAV-ie targeting the inner ear stem cells are successfully achieved. Single-cell nuclear sequencing and lineaging tracing results showed that the majority of new Atoh1-derived HCs are in a state of initiating differentiation, while GP (Gfi1, Pou4f3) and GPS (Gfi1, Pou4f3, and Six1) enhanced the Atoh1-induced new HCs into inner and outer HCs. Moreover, the patch-clamp analysis indicated that newborn inner HCs induced by GPAS forced expression have similar electrophysiological characteristics to those of native inner HCs. Also, GPAS can induce HC regeneration in the HC-damaged mice model. In summary, the study demonstrates that AAV-mediated co-regulation of multiple genes, such as GPAS, is an effective means to achieve functional HC regeneration in the mouse cochlea.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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