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Electrode implantation trauma (EIT) initiates fibrosis by over‐expression of TGF‐β1 and activation of the Wnt/β‐catenin pathway in an in vitro model of cochlear implantation
Author(s) -
Infante Esperanza Bas,
Gupta Chhavi,
Goldstein Bradley,
Van De Water Thomas R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.599.6
Subject(s) - ctgf , cochlea , catenin , microbiology and biotechnology , sox2 , wnt signaling pathway , chemistry , biology , anatomy , medicine , signal transduction , growth factor , embryonic stem cell , receptor , biochemistry , gene
Background The insertion of a cochlear implant (CI) electrode array can be associated with an inflammatory response that induces loss of auditory hair cells and growth of fibrotic tissue around the electrode array. From previous work we know that trauma to the cochlea induces expression of TGF‐β. We hypothesize that TGF‐β1 co‐operates with the Wnt/β‐catenin pathway to elicit fibrosis. TGF‐β is known to activate the PI3K pathway, which can stabilize β‐catenin. Methods Cochleae from 3 days rat pups were divided into: 1) Control untreated; 2) TGF‐β1; 3) TGF‐β3; 4) LY294002 (LY); 5) EIT; 6) EIT+ TGF‐β1; 7) EIT+ TGF‐β3; 8) EIT+ LY. mRNA levels of Axin2; Wnt4, Wnt5b and CTGF were measured. Confocal studies for α‐SMA), presence of stress fibers, and expression of SOX2 were carried out in organ of Corti (oC) explants and lateral wall tissues (LW) after 96h of incubation. Results EIT upregulated CTGF expression in oC and LW tissues. Axin2 mRNA levels were increased in oC explants treated with TGF‐β1 or 3. EIT downregulated Wnt5b expression in oC explants. Increase of SOX2 levels ocurred near the wound area and in LY treated explants. EIT induced expression of α‐SMA and actin stress fibers in oC explants. TGF‐β1 induced expression of α‐SMA. LY treatment reduced α‐SMA levels and the presence of stress fibers, however many apoptotic bodies were present in these explants. Conclusion Induction of EIT in the cochlea triggers a fibrogenic response as part of the wound healing process, in which TGF‐βs assume a key role. oC and LW cells respond differently to a mechanical trauma induced by an electrode. Our results suggest increased activation of the Wnt/β‐catenin pathway by EIT in oC explants, exacerbated by TGF‐β1 treatment, which leads to cell growth and differentiation. Wnt pathways do not appear to participate in the fibrotic response initiated in the LW tissues.