Odontoblast death drives cell-rich zone-derived dental tissue regeneration

Lijuan Zhao, Shinichirou Ito, Atsushi Arai, Nobuyuki Udagawa, Kanji Horibe, Miroku Hara, Daisuke Nishida, Akihiro Hosoya, Rinya Masuko, Koji Okabe, Masashi Shin, Xianqi Li, Koichi Matsuo, Shinichi Abe, Satoru Matsunaga, Yasuhiro Kobayashi, Hideaki Kagami, Toshihide Mizoguchi

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Severe dental tissue damage induces odontoblast death, after which dental pulp stem and progenitor cells (DPSCs) differentiate into odontoblast-like cells, contributing to reparative dentin. However, the damage-induced mechanism that triggers this regeneration process is still not clear. We aimed to understand the effect of odontoblast death without hard tissue damage on dental regeneration. Herein, using a Cre/LoxP-based strategy, we demonstrated that cell-rich zone (CZ)-localizing Nestin-GFP-positive and Nestin-GFP-negative cells proliferate and differentiate into odontoblast-like cells in response to odontoblast depletion. The regenerated odontoblast-like cells played a role in reparative dentin formation. RNA-sequencing analysis revealed that the expression of odontoblast differentiation- and activation-related genes was upregulated in the pulp in response to odontoblast depletion even without damage to dental tissue. In this regenerative process, the expression of type I parathyroid hormone receptor (PTH1R) increased in the odontoblast-depleted pulp, thereby boosting dentin formation. The levels of PTH1R and its downstream mediator, i.e., phosphorylated cyclic AMP response element-binding protein (Ser133) increased in the physically damaged pulp. Collectively, odontoblast death triggered the PTH1R cascade, which may represent a therapeutic target for inducing CZ-mediated dental regeneration.

Original languageEnglish
Article number116010
Publication statusPublished - 2021 Sept


  • Cell-rich zone
  • Dental tissue regeneration
  • Nestin
  • Odontoblast
  • Odontoblast-like cell
  • PTH1R

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology


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