Wnt-directed CXCL12-expressing apical papilla progenitor cells drive tooth root formation

Mizuki Nagata, Gaurav T. Gadhvi, Taishi Komori, Yuki Arai, Hiroaki Manabe, Angel Ka Yan Chu, Ramandeep Kaur, Meer Ali, Yuntao Yang, Chiaki Tsutsumi-Arai, Yuta Nakai, Yuki Matsushita, Nicha Tokavanich, W. Jim Zheng, Joshua D. Welch, Noriaki Ono and Wanida Ono ()
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Mizuki Nagata: University of Texas Health Science Center at Houston School of Dentistry
Gaurav T. Gadhvi: University of Michigan
Taishi Komori: University of Texas Health Science Center at Houston School of Dentistry
Yuki Arai: University of Texas Health Science Center at Houston School of Dentistry
Hiroaki Manabe: University of Texas Health Science Center at Houston School of Dentistry
Angel Ka Yan Chu: University of Michigan
Ramandeep Kaur: University of Michigan School of Dentistry
Meer Ali: University of Texas Health Science Center at Houston
Yuntao Yang: University of Texas Health Science Center at Houston
Chiaki Tsutsumi-Arai: University of Texas Health Science Center at Houston School of Dentistry
Yuta Nakai: University of Texas Health Science Center at Houston School of Dentistry
Yuki Matsushita: Nagasaki University Graduate School of Biomedical Sciences
Nicha Tokavanich: University of Texas Health Science Center at Houston School of Dentistry
W. Jim Zheng: University of Texas Health Science Center at Houston
Joshua D. Welch: University of Michigan
Noriaki Ono: University of Texas Health Science Center at Houston School of Dentistry
Wanida Ono: University of Texas Health Science Center at Houston School of Dentistry

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The tooth root is a critical component of the tooth anchored to surrounding alveolar bones. Tooth root formation is driven by cells in the apical papilla (AP) that generate new dentin-forming odontoblasts at the root-forming front. Mesenchymal stem cells have been isolated from AP for regenerative use; however, how AP cells physiologically coordinate tooth root formation remains undefined. We find that CXCL12+ cells emerge in AP under hypoxic environments at the onset of tooth root formation. Using Cxcl12-creER-based cell-lineage analysis, we further find that CXCL12+ AP cells contribute not only to odontoblasts but also to cementum-forming cementoblasts of the elongating root, while showing plasticity to alveolar bone osteoblasts under regenerative conditions. Canonical Wnt inactivation inhibits odontoblast fates of CXCL12+ AP cells and induces substantial root truncation, with their aberrant fibroblast fates suppressed by TGF-β receptor inhibitor galunisertib. Therefore, CXCL12+ AP cells maintain odonto-cementogenic fates in a Wnt-dependent manner, identifying these cells as pivotal dental mesenchymal progenitor cells driving tooth root formation with substantial plasticity.

Date: 2025
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DOI: 10.1038/s41467-025-61048-x

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