TGF β-1 and WNT Signaling Pathways Collaboration Associated with Cochlear Implantation Trauma-Induced Fibrosis.

The crosstalk between TGF-β1 and WNT pathways has been proven to regulate aspects of the development and tissue homeostasis processes. Recently, it has been demonstrated this collaboration also takes place during fibrotic diseases, where TGF-β1 activates the WNT/β-catenin pathway that results in dedifferentiation of fibroblasts into myofibroblasts, increased production of extracellular matrix components and fibrosis. Independent studies show the functions of these molecules during the development of the inner ears in several different species. However, little is known about the collaboration between TGF-β1 and WNT in the injured inner ear and particularly how this collaboration affects the fibrotic process that often occurs following cochlear implantation. First, we used a cochlear explant model to study the effect of electrode insertion trauma and TGF-β1 signaling in activation of the WNT pathway. Finally, adult TopGal mutant mice were used in vivo to track the activation of the WNT/β-catenin in response to EIT. A chronic inflammatory response, increased cell proliferation and tissue remodeling are hallmarks of fibrotic disease. This study explores and highlights the collaboration between the TGF-β1 and WNT pathways in the trauma-initiated fibrotic process within the implanted cochlea. WNT signaling is involved in the development of the inner ear and therefore a potential target in hair cell regeneration therapies. However, in light of our observations from the current study, manipulation of the WNT pathway by gene therapy techniques in the pathological ear seems a very complex process with an increased risk of inducing excessive fibrosis thereby compromising the efficacy of implant function. Anat Rec, 303:608-618, 2020. © 2019 American Association for Anatomy.