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Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

Wenyan Li1, Jingfang Wu2, Jianming Yang3

  • 1Department of Otorhinolaryngology, Department of Otology and Laryngology, Harvard Medical School, Boston MA 02115; Eaton Peabody Laboratory, Massachusetts Eye & Ear Infirmary, Boston MA 02114;

Proceedings of the National Academy of Sciences of the United States of America
|December 24, 2014
PubMed

Insights

Notch inhibition spurs the regeneration of auditory hair cells (HCs) by activating Lgr5(+) progenitor cells. This discovery offers a new pathway for hearing recovery through HC regeneration by modulating Notch and Wnt signaling.

Area of Science:

  • Otolaryngology
  • Regenerative Medicine
  • Developmental Biology

Background:

  • Hair cell (HC) regeneration is crucial for hearing recovery.
  • Mechanisms controlling postnatal cochlear progenitor cell proliferation and HC differentiation are not fully understood.
  • Identifying progenitor cells and their activation pathways is key for therapeutic strategies.

Purpose of the Study:

  • To investigate the role of Notch signaling in cochlear progenitor cell proliferation and hair cell regeneration.
  • To identify the specific progenitor cells responsible for Notch inhibition-induced hair cell regeneration.
  • To elucidate the molecular interplay between Notch and Wnt pathways in cochlear regeneration.

Main Methods:

  • Inhibition of Notch signaling in neonatal mouse cochlea, both in vivo and in vitro.
  • Lineage tracing to track the origin of proliferating supporting cells (SCs) and newly generated HCs.
  • Analysis of Wnt signaling pathway activation in response to Notch inhibition.

Main Results:

  • Notch inhibition successfully induced proliferation of supporting cells and mitotic regeneration of hair cells.
  • Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells were identified as the primary source of regenerated HCs.
  • Notch inhibition was shown to release the suppression on canonical Wnt signaling, promoting Lgr5(+) progenitor cell proliferation and HC generation.

Conclusions:

  • Notch signaling normally restricts the regenerative potential of postnatal cochlear progenitor cells.
  • Interrupting the Notch-Wnt pathway interaction provides a novel strategy for hair cell regeneration.
  • This research opens a new avenue for developing therapies for hearing loss by regenerating auditory hair cells.
Keywords:
Notch1hair cellsinner earproliferationβ-catenin

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