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

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

Affiliations

¹Institute for Oral Science, Matsumoto Dental University, Nagano, Japan

²Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Tokyo, Japan

³Department of Orthodontics, Matsumoto Dental University, Nagano, Japan

⁴Department of Oral Biochemistry, Matsumoto Dental University, Nagano, Japan

⁵Department of Oral Histology, Matsumoto Dental University, Nagano, Japan

⁶Department of Oral Diagnostics and Comprehensive Dentistry, Matsumoto Dental University Hospital, Nagano, Japan

⁷Oral Health Science Center, Tokyo Dental College, Tokyo, Japan

⁸Division of Histology, School of Dentistry, Health Science University of Hokkaido, Hokkaido, Japan

⁹JEOL Ltd., Tokyo, Japan

¹⁰Section of Cellular Physiology, Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan

¹¹Oral Medicine Center, Fukuoka Dental College, Fukuoka, Japan

¹²Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Nagano, Japan

¹³Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan

¹⁴Department of Anatomy, Tokyo Dental College, Tokyo, Japan

Abstract and keywords

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; Odontoblast; Odontoblast-like cell; Nestin; PTH1R

Links

DOI: 10.1016/j.bone.2021.116010

PubMed: 34020080

WoS: 000670351300001

History

Received: 2021-04-15

Revised: 2021-05-10

Accepted: 2021-05-12

Online: 2021-05-18

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