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PhD Thesis Defense Seminar

K-307 Auditorium (3-6408), University of Rochester Medical Center

“Identification of PAI-1 as a Biological Target for the Promotion of Scarless Flexor Tendon Healing”

Presented by: Youssef Farhat
Supervised by: Prof. Hani Awad

Flexor tendon injuries, such as deep cuts to the hands, pose unique challenges due to their tendency to form debilitating adhesions, which are a type of scar tissue that severely restricts flexion of the affected fingers. Evidence exists that tendon adhesions are largely precipitated by the pleiotropic growth factor, Transforming Growth Factor Beta 1 (TGF-β1), but the effects of TGF-β1 are poorly understood in the context of tendon healing. Using an in vitro model of tendon healing, it was found that TGF-β1 causes gene expression changes in tendon cells that are consistent with scar tissue and adhesion formation, including upregulation of Plasminogen Activator Inhibitor 1 (PAI-1), a master regulator of protease activity in the fibrinolytic system. Notably, treatment of wild type flexor tendon cells with TGF-β1 reduced the protease activity of tissue-Plasminogen Activator (tPA), Plasmin, and Matrix Metalloproteinases (MMPs) by as much as 96%. In contrast, the protease activity of flexor tendon cells from PAI-1 knockout (PAI-1 KO) mice did not decrease after treatment with TGF-β1, suggesting that PAI-1 was essential to the suppression of protease activity by TGF-β1. Using a clinically-relevant mouse model of flexor tendon injuries, it was demonstrated histologically that PAI-1 KO mice had an average of 59% less adhesions, increased cellularity, and increased tendon bulk volume two weeks after injury compared to wild type mice. These results support the hypothesis that PAI-1 inhibition may be an effective strategy for the treatment of flexor tendon adhesions, and warrant a more detailed investigation of its effects on tendon strength and the biomechanics of joint flexion.