Tendon injuries are common disorders that can significantly impact people’s lives. Unfortunately, the limited regenerative ability of tendons results in tissue healing in a scar-mediated manner. The current therapeutic strategies fail to fully recover the functions of the injured tendons, and as such, the conception of ‘scarless healing’ has gained prominent attention in the field of regenerative medicine. Interestingly, injured fetal tendons possess the capability to heal through regeneration, which builds an ideal blueprint for adult tendon regeneration. Studies have shown that fetal biochemical cues have the potential to improve adult tendon healing. Here we review the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration.

Plain language summary

We reviewed the biological factors that contribute to fetal tendon regeneration and how manipulation of these biochemical cues in the adult tendon healing process could achieve regeneration. The results showed that inflammation and TGF-β level are the main elements involved in fetal tendon regeneration. Experimental manipulation of these biochemical cues in the adult tendon healing process demonstrated that although the blockade of TGF-β1, TGF-β2 and inflammation reduced scar tissue in adult tendon healing, this inhibition also destroyed the mechanical properties of the tendons. An effective alternative is regulating the specific downstream profibrotic effectors of both TGF-β1 and inflammation, which is preferable to those that completely inhibit these factors. Finally, TGF-β3 is a master regulator allowing a shift from adult scar healing to scarless healing, and the administration of TGF-β3 is a viable strategy to promote adult regenerative healing. In terms of mechanisms, TGF-β3 can activate Smad7 and inhibit the JNK/c-Jun signaling pathway to promote tendon regenerative healing.

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Vol. 18, No. 10

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Received 16 July 2023

Accepted 22 August 2023

Published online 6 September 2023

Published in print October 2023

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Author contributions

Han Li, H Chen, S Li, L Jiang, Y Chen, Hong Li and H Pan designed the present manuscript. Han Li created the figures and wrote the manuscript. H Chen, S Li, L Jiang, Y Chen, Z Feng and H Pan performed a literature search and selected the studies to be performed. Han Li revised including the manuscript. All authors contributed to the article and approved the submitted version.

Financial & competing interests disclosure

This work was supported by Sichuan Science and Technology Program (2022YFS0609). Support from the following four projects is also gratefully acknowledged: the Sichuan Provincial Science and Technology Plan Project (2022NSFSC0688) and the Luzhou Municipal Government-Southwest Medical University Joint Project (2021LZXNYD-J10), Southwest Medical University Applied Basic Fundamental Research Project (2021ZKMS050), Hejiang County People’s Hospital – Southwest Medical University Science and Technology Strategic Cooperation Project (2022HJXNYD07).The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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From fetal tendon regeneration to adult therapeutic modalities: TGF-β3 in scarless healing

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