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Notch signaling pathway in keloid disease: Enhanced fibroblast activity in a J agged‐1 peptide‐dependent manner in lesional vs. extralesional fibroblasts
Author(s) -
Syed Farhatullah,
Bayat Ardeshir
Publication year - 2012
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1524-475x.2012.00823.x
Subject(s) - notch signaling pathway , keloid , fibroblast , wound healing , angiogenesis , receptor , chemistry , cell , microbiology and biotechnology , cancer research , in vitro , pathology , immunology , biology , medicine , biochemistry
Keloid disease ( KD ) is a fibroproliferative disorder of unknown etiopathogenesis with ill‐defined treatment. There is increasing evidence to suggest that aberrant N otch signaling may contribute directly to skin pathogenesis and altered expression of N otch receptors identified in KD . Therefore, the aim of this study was to investigate the N otch signaling pathway in KD compared to normal skin ( NS ). In this study, we employed in vitro primary cell culture models to elucidate the role of N otch signaling in 44 tissue samples from patients with KD split into keloid and extralesional ( EL ) samples (internal control) from the same patients, and six NS tissue samples (external control). We show the presence of a significant ( p < 0.05) up‐regulation of N otch receptors and ligand J agged‐1 ( JAG ‐1) in KD compared to EL and NS tissue samples. Cell spreading, attachment, and proliferation were significantly ( p < 0.05) reduced in JAG ‐1 antisense‐treated primary dermal fibroblasts isolated from KD and treated with γ‐secretase inhibitor (blocks proteolytic cleavage and activation of N otch), evaluated by real‐time cell analyzer ( RTCA ) on a microelectronic sensory array. In contrast, extralesional skin fibroblasts ( ELF ) treated with recombinant human JAG ‐1 (rh‐ JAG ‐1) peptide showed significant ( p < 0.05) enhancement of cell spreading, attachment, and proliferation in RTCA . Activation/inhibition of JAG ‐1 and N otch signaling significantly ( p < 0.05) altered the behavior of primary keloid fibroblasts and ELF , in cell migration (using a scratch wound assay), invasion (using a 3 D invasion assay), and angiogenesis (in vitro coculture tube formation assay). In conclusion, this is the first study to demonstrate a potential role for the N otch signaling pathway in KD progression and that targeting this pathway may provide a novel strategy for treatment of KD .