Autocrine ECM molecules establish MSC quiescence during incisor development by disrupting WNT ligand trafficking process

Zexi Chen, Meilian Cai, Yuling Wang, Xuan Li, Yongwen He, Hongji Pu, Juan Huang, Ling Ye, Ruili Yang (), Junjun Jing () and Hu Zhao ()
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Zexi Chen: Peking University, Academy for Advanced Interdisciplinary Studies
Meilian Cai: Chinese Institute for Brain Research
Yuling Wang: Chinese Institute for Brain Research
Xuan Li: Sichuan University, State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology
Yongwen He: Qujing Medical College
Hongji Pu: Qujing Medical College
Juan Huang: Chinese Institute for Brain Research
Ling Ye: Sichuan University, State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology
Ruili Yang: National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Department of Orthodontics, Peking University School and Hospital of Stomatology
Junjun Jing: Sichuan University, State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology
Hu Zhao: Chinese Institute for Brain Research

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Stem cells support homeostasis and injury repair of adult organs. It remains unclear when and how adult stem cells form during development. Here, we discover that incisor mesenchymal stem cells, marked by an extracellular matrix molecule Smoc2, establish their identity and quiescence between E14.5 and E16.5, and persist into adulthood. They support both embryonic tooth development and postnatal organ turnover. Concurrently, the incisor mesenchyme evolves from a homogenous dental papilla into a heterogeneous dental pulp consisting of a complete lineage hierarchy, which persists into adulthood. Smoc2 and its homologous molecule Smoc1 are indispensable for maintaining the quiescence and hierarchy of mesenchymal stem cells. They function by disrupting the binding between canonical WNT ligands and glypican, a process critical for transporting hydrophobic WNT ligands within the aqueous niche. In conclusion, mesenchymal stem cells establish their quiescence during development through autocrine extracellular matrix molecules to keep canonical WNT ligands from accessing them.

Date: 2025
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DOI: 10.1038/s41467-025-65705-z

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