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

doi:10.1016/j.bone.2021.116010

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

Bone. 2021 Sep:150:116010. doi: 10.1016/j.bone.2021.116010. Epub 2021 May 18.

Authors

Lijuan Zhao¹, Shinichirou Ito², Atsushi Arai³, Nobuyuki Udagawa⁴, Kanji Horibe⁵, Miroku Hara⁶, Daisuke Nishida⁷, Akihiro Hosoya⁸, Rinya Masuko⁹, Koji Okabe¹⁰, Masashi Shin¹¹, Xianqi Li¹², Koichi Matsuo¹³, Shinichi Abe¹⁴, Satoru Matsunaga¹⁴, Yasuhiro Kobayashi¹, Hideaki Kagami¹, Toshihide Mizoguchi¹⁵

Affiliations

¹ Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
² Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Tokyo, Japan.
³ Department of Orthodontics, Matsumoto Dental University, Nagano, Japan.
⁴ Department of Oral Biochemistry, Matsumoto Dental University, Nagano, Japan.
⁵ Department of Oral Histology, Matsumoto Dental University, Nagano, Japan.
⁶ Department of Oral Diagnostics and Comprehensive Dentistry, Matsumoto Dental University Hospital, Nagano, Japan.
⁷ Oral Health Science Center, Tokyo Dental College, Tokyo, Japan.
⁸ Division of Histology, School of Dentistry, Health Science University of Hokkaido, Hokkaido, Japan.
⁹ JEOL Ltd., Tokyo, Japan.
¹⁰ Section of Cellular Physiology, Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan.
¹¹ Section of Cellular Physiology, Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan; Oral Medicine Center, Fukuoka Dental College, Fukuoka, Japan.
¹² Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Nagano, Japan.
¹³ Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan.
¹⁴ Department of Anatomy, Tokyo Dental College, Tokyo, Japan.
¹⁵ Institute for Oral Science, Matsumoto Dental University, Nagano, Japan; Oral Health Science Center, Tokyo Dental College, Tokyo, Japan. Electronic address: tmizoguchi@tdc.ac.jp.

PMID: 34020080
DOI: 10.1016/j.bone.2021.116010

Abstract

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.

Keywords: Cell-rich zone; Dental tissue regeneration; Nestin; Odontoblast; Odontoblast-like cell; PTH1R.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Dental Pulp
Dentin*
Odontoblasts*
Stem Cells
Wound Healing