What the review is

Yang, Zhang, Gao, Wang and Wu, spanning Central South University (Xiangya), Capital Medical University and the Southern University of Science and Technology, published a review in the International Journal of Oral Science (received April 28, 2026, accepted July 27, 2026, doi:10.1038/s41368-026-00462-3, open access). It surveys how mechanical stress, not just genetic programs and signaling networks, regulates dentofacial development: crown formation, root morphogenesis, eruption and replacement, and maxillomandibular bone remodeling. This is a synthesis of existing work, not a new experiment.

The framework

The authors group the machinery into three modules that are redeployed stage by stage. Upstream, integrin-focal adhesion complexes sense the extracellular matrix. Mechanosensitive ion channels, named as Piezo1/2 and TRPV1/4, convert membrane tension into cation influx. Downstream, the Hippo pathway effectors YAP/TAZ shuttle between nucleus and cytoplasm and govern proliferation, differentiation and morphogenesis. The same cascade recurs at each stage, epithelial invagination, crown morphogenesis, root formation, eruption, jaw remodeling, but each mechanical microenvironment draws a different response.

One concrete example the review highlights, from Miyazaki and colleagues (Sci Rep 2019): in stem cells from human exfoliated deciduous teeth, hydrostatic pressure promotes odontogenic differentiation by activating Piezo1, which coordinates Wnt signaling and ciliogenesis. The Piezo1 agonist Yoda1 suppresses proliferation, induces primary cilia formation and drives nuclear translocation of RUNX2, and silencing Piezo1 abolishes the pressure-induced odontogenic effect. This is in vitro human deciduous-tooth cells, not a regenerative outcome in an animal.

Stress sets the clock on tooth replacement

The section most relevant to the third dentition concerns the successional dental lamina, the structure that produces the replacement tooth. The review describes work from Wu and colleagues (EMBO Journal, doi:10.15252/embj.2019102374) and Li and colleagues (J Dent Res 2023): before the deciduous tooth erupts, biomechanical stress between it and the successional dental lamina keeps that lamina quiescent by upregulating an Integrin beta1-Runx2-Fibulin-1 program in dental follicle mesenchymal cells. When the deciduous tooth erupts and the stress drops, the program falls, and development of the permanent tooth initiates. On this account, the natural replacement tooth is held in reserve by a mechanical brake, and its release is a mechanical event, not purely a molecular timer. This is mammalian developmental biology, demonstrated in model systems, not a human intervention.

Two corrections the record already supports

The review restates two findings that cut against popular simplifications. First, eruption does not need a root: rootless teeth, congenitally absent or experimentally induced, erupt normally in humans and multiple animal models. The accepted driver is polarized remodeling of the surrounding alveolar bone, coronal resorption and basal deposition, orchestrated by the dental follicle, a picture with classic experimental backing from Cahill and Marks. Second, removing bite force is not itself a signal: bilateral truncation of rodent incisors raises mesenchymal stem cell proliferation and eruption rate, but unilateral truncation produces no significant change (An et al., Nat Commun 2018), so simple force elimination does not explain the proliferative response.

Boundary

Everything load-bearing here is either a review-level claim or evidence from rodents, other animal models, and cultured human cells. There is no clinical data, no regenerated human tooth, and no demonstration that manipulating mechanical stress alone can start or complete tooth replacement. The review itself closes by naming the gaps: mechanistic maps are fragmented across stages, and in vivo mechanical measurement in developing human dentition remains hard. Mechanics is presented as a modulator layered on the signaling programs the field already tracks.

What it changes

For the root organoids program, the practical message is that force is a design variable. Root formation and periodontal ligament homeostasis both run through mechanotransduction: Gli1-positive apical stem and progenitor cells supply root dentin, pulp and periodontal tissues and sit at the node where mechanical signals are transduced, and periodontal ligament cells read load through Piezo1, with TRPV4 shifting periodontal ligament stem cells toward a pro-inflammatory, pro-osteoclastic state under compression. A root organoid or reassociated tooth construct that is never mechanically loaded is modeling only half the system. For the bioengineered tooth germ program, the successional lamina work is a reminder that natural replacement timing is gated by stress release, which any bioengineered replacement scheme will have to reproduce or override. No program tier moves on review-level evidence; the field assessment stands at /field/.

Provenance: grounded in the complete open-access text (PMC13529664, CC BY-NC-ND). See /method/.