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

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-beta 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-beta 1, TGF-beta 2 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-beta 1 and inflammation, which is preferable to those that completely inhibit these factors. Finally, TGF-beta 3 is a master regulator allowing a shift from adult scar healing to scarless healing, and the administration of TGF-beta 3 is a viable strategy to promote adult regenerative healing. In terms of mechanisms, TGF-beta 3 can activate Smad7 and inhibit the JNK/c-Jun signaling pathway to promote tendon regenerative healing.

Automated 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-beta 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-beta 1, TGF-beta 2 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-beta 1 and inflammation, which is preferable to those that completely inhibit these factors. Finally, TGF-beta 3 is a master regulator allowing a shift from adult scar healing to scarless healing, and the administration of TGF-beta 3 is a viable strategy to promote adult regenerative healing.