PI3K-Akt signalling regulates Scx-lineage tenocytes and Tppp3-lineage paratenon sheath cells in neonatal tendon regeneration

Atsushi Goto, Shingo Komura (), Koki Kato, Rie Maki, Akihiro Hirakawa, Hitomi Aoki, Hiroyuki Tomita, Jumpei Taguchi, Manabu Ozawa, Takahide Matsushima, Akio Kishida, Tsuyoshi Kimura, Hiroshi Asahara, Yuuki Imai, Yasuhiro Yamada and Haruhiko Akiyama
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Atsushi Goto: Gifu University Graduate School of Medicine
Shingo Komura: Gifu University Graduate School of Medicine
Koki Kato: Gifu University Graduate School of Medicine
Rie Maki: Gifu University Graduate School of Medicine
Akihiro Hirakawa: Gifu University Graduate School of Medicine
Hitomi Aoki: Gifu University Graduate School of Medicine
Hiroyuki Tomita: Gifu University Graduate School of Medicine
Jumpei Taguchi: University of Tokyo
Manabu Ozawa: University of Tokyo
Takahide Matsushima: Institute of Science Tokyo
Akio Kishida: Institute of Science Tokyo
Tsuyoshi Kimura: Toyo University
Hiroshi Asahara: Institute of Science Tokyo
Yuuki Imai: Ehime University
Yasuhiro Yamada: The University of Tokyo
Haruhiko Akiyama: Gifu University Graduate School of Medicine

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

Abstract: Abstract Tendon injuries are frequently occurring disorders; it is clinically important to enhance tendon regeneration and prevent functional impairment post-injury. While tendon injuries in children heal quickly with minimal scarring, those in adults heal slowly and are accompanied by fibrotic scarring. Therefore, investigating the healing mechanisms after tendon injury, and identifying the factors that regulate the inherent regenerative capacity of tendons are promising approaches to promoting tendon regeneration. Here, we identify that the PI3K-Akt signalling pathway is preferentially upregulated in injured neonatal murine Achilles tendons. Inhibition of PI3K-Akt signalling in a neonatal murine Achilles tendon rupture model decreases cell proliferation and migration in both Scx-lineage intrinsic tenocytes and Tppp3-lineage extrinsic paratenon sheath cells. Moreover, the inhibition of PI3K-Akt signalling decreases stemness and promotes mature tenogenic differentiation in both Scx- and Tppp3-lineage cells. Collectively, these results suggest that PI3K-Akt signalling plays a pivotal role in neonatal tendon regeneration.

Date: 2025
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DOI: 10.1038/s41467-025-59010-y

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