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Single-Cell Virtual Perturbation Screening Identifies STAT3 as a Key Regulator of Dentinogenesis.

Yanfei Zhu¹, Hongyuan Xu¹, Zijian Zhang¹

¹Center of Craniofacial Orthodontics, Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.

Cell Proliferation

|April 15, 2026

Summary

Signal transducer and activator of transcription 3 (STAT3) is crucial for dentine formation. STAT3 regulates odontoblast differentiation and activates Wnt/β-catenin signaling, offering targets for dentine regeneration therapies.

Keywords:

STAT3 WNT2B Wnt signalling pathway dentine development dentinogenesis in silico perturbation odontoblast differentiation

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Area of Science:

Cell Biology
Developmental Biology
Genetics

Background:

Dentine formation (dentinogenesis) is a complex process involving odontoblast differentiation and mineralization, tightly controlled by signaling pathways.
Understanding the molecular mechanisms governing dentinogenesis is crucial for addressing developmental disorders and advancing regenerative strategies.

Purpose of the Study:

To identify key regulators of odontoblast lineage development and dentinogenesis.
To elucidate the role of signal transducer and activator of transcription 3 (STAT3) in dentinogenesis.
To explore STAT3's downstream targets and signaling pathways involved in dentine formation.

Main Methods:

Single-cell RNA sequencing to define progenitor populations.
CellRank and SCENIC for fate mapping and regulon analysis.
In silico perturbations, shRNA silencing, pharmacological modulation, conditional knockout mice, RNA-seq, and ChIP assays.

Main Results:

EFNB2+ mesenchymal cells identified as primary odontogenic progenitors.
STAT3 identified as a pivotal regulator of odontoblast lineage.
STAT3 is essential for dental mesenchymal cell proliferation and differentiation; Stat3 knockout leads to dentine dysplasia.
STAT3 directly activates WNT2B, thereby regulating Wnt/β-catenin signaling.

Conclusions:

STAT3 is a critical regulator of dentinogenesis.
STAT3's role in activating Wnt/β-catenin signaling is essential for proper dentine formation.
STAT3 and WNT2B represent potential therapeutic targets for dentine developmental disorders and regeneration.