Notch signaling pathway in keloid disease: Enhanced fibroblast activity in a J agged‐1 peptide‐dependent manner in lesional vs. extralesional fibroblasts

• Published in: Wound repair and regeneration Vol. 20; no. 5; pp. 688 - 706
• Main Authors: Syed, Farhatullah, Bayat, Ardeshir
• Format: Journal Article
• Language: English
• Published: 01.09.2012
• ISSN: 1067-1927; 1524-475X
• DOI: 10.1111/j.1524-475X.2012.00823.x

Abstract 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 .