2. Academic Validation
  3. Conditional Overexpression of Serpine2 Promotes Hair Cell Regeneration from Lgr5+ Progenitors in the Neonatal Mouse Cochlea

Conditional Overexpression of Serpine2 Promotes Hair Cell Regeneration from Lgr5+ Progenitors in the Neonatal Mouse Cochlea

  • Adv Sci (Weinh). 2025 Mar 17:e2412653. doi: 10.1002/advs.202412653.
Hairong Xiao 1 2,  Jiheng Wu 1,  Lixuan Huang 1,  Ying Ma 1,  Leilei Wu 1,  Yanqin Lin 1 2,  Zixuan Ye 1,  Xin Tan 1,  Xujun Tang 1,  Wei Tong 1,  Mingchen Dai 1,  Yintao Wang 1,  Xia Sheng 3 4,  Renjie Chai 1 2 5 6 7,  Shasha Zhang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
  • 2 Southeast University Shenzhen Research Institute, Shenzhen, 518063, China.
  • 3 School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4 Department of Environmental Health, School of Environmental Science and Engineering, Hainan University, Haikou, 570228, China.
  • 5 Institute for Stem Cells and Regeneration, Chinese Academy of Science, Beijing, 100081, China.
  • 6 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
  • 7 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
PMID: 40091489 DOI: 10.1002/advs.202412653
Abstract

Neonatal cochlear Lgr5+ progenitors retain limited hair cells (HCs) regenerative capacity, but the regulatory network remains incompletely defined. Serpin family E member 2 (Serpine2) is shown to participate in regulating proliferation and differentiation of cochlear Lgr5+ progenitors in the previous in vitro study. Here, the expression pattern and in vivo roles of Serpine2 in HC regeneration are explored by transgenic mice. It is found that Serpine2 is expressed in the mouse cochlea after birth with a downward trend as the mice age. In addition, Serpine2 conditional overexpression in vivo in Lgr5+ progenitors of neonatal mice cochlea results in an increased number of ectopic HCs in a dose-dependent manner. Serpine2 knockdown ex vivo and in vivo can inhibit HC regeneration. EdU assay and lineage tracing assay demonstrate these ectopic HCs likely originate from Lgr5+ progenitors through direct transdifferentiation rather than through mitotic regeneration. Moreover, single-nucleus RNA Sequencing analysis and mRNA level validation reveal that conditionally overexpressed Serpine2 likely induces HC regeneration via inhibiting sonic Hedgehog (SHH) signal pathway and inducing Atoh1 and Pou4f3 transcription factor. In brief, these data indicate that Serpine2 plays a pivotal role in HC regeneration from Lgr5+ progenitors in the neonatal mouse cochlea, and this suggests a new avenue for future research into HC regeneration.

Keywords

Lgr5+ progenitors; Serpine2; hair cells; regeneration.

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