Reversal of phenotype and plasticity of myofibroblasts to target peri-implantation fibrosis

Abstract

Peri-implant fibrosis poses a setback in regenerative medicine. Our group has described the anti-fibrotic effects of suberoylanilide hydroxamic acid (SAHA). When administered in the presence of transforming growth factor (TGF)-?1, SAHA prevented fibroblast ? myofibroblast transition. However, SAHA no longer exerted anti-fibrotic effects when myofibroblasts were treated with TGF?1 prior to SAHA. Many cytokines impact cells in pulses, yet current protocols employ continuous TGF?1 exposure to cells. We therefore evaluated the effects of pulsatile TGF?1 treatment in fibroblast ? myofibroblast differentiation to better assess SAHA?s anti-fibrotic effects. We demonstrated that a single 0.5h TGF?1 pulse was sufficient to effect long-term changes towards the myofibroblast phenotype, potentiated by a second pulse 24h later. Revisiting SAHA?s effects in TGF?1 pulses we observed the normalization of TGF?1-effects, and further presented evidence of compromised myofibroblast motility. Our findings contribute to the understanding of myofibroblast induction, maintenance and the use of an FDA-approved agent to curb fibrosis.