Plastic Surgery Research Council
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THE ABERRANT NOTCH SIGNALING CONTRIBUTE TO SCAR HYPERPLASIA THROUGH MODULATING BIOACTIVITY OF KERATINOCYTES
Presenter: Wei Xia, MD, MS
Co-Authors: DIAO J; XIA W
Fourth Military Medical University Xijing Hospital

Researches of past decades have shown that aberrant proliferation, differentiation and secretion of epidermis play an important role in Hypertrophic scar pathogenesis. Notch signaling functions as a molecular switch that controls the differentiation and proliferation of keratinocytes between skin layers during the process of epidermal development, self-renewal and repair. So we speculated that Notch signal pathway may be involved in scar hyperplasia. Methods Hypertrophic scars specimens were collected from 8 Chinese patients, the hypertrophic scars of rabbit ears were reproduced, and in vitro, keratinocytes serum stimulation model was employed to mimic one the components of acute wound microenvironment. Results In the epidermis of hypertrophic scars, compared with the normal skins, the expressions of integrin?1, K14 and K19 were significantly down regulated, while the expressions of Notch1, Jagged1 and P21 were significantly up regulated, but P63 expression was down regulated. In the hypertrophic scar rabbit model, the local application of DAPT (the canonical Notch pathway inhibitor) could inhibit scar hyperplasia, evidenced by the decrease of scar elevation index and dermal fibroblast number. This effect could be related to the restore proliferation and inhibited differentiation of epidermis, with increasing the expression of K14 and K19, and decreasing Involucrin expression. In keratinocytes serum stimulation model, consistent with the vivo findings, activated Notch signaling induced keratinocyte over-differentiation while decreased proliferation. Interestingly, the expressions of multiple profibrotic growth factors (TGF≤-?1, TGF≤-?2, IGF-1, CTGF≤, VEGF and EGF) were closely related to the profile of Notch signaling. Jagged1 peptides promote production of these profibrotic growth factors with bioactivity. Conclusion Notch signal pathway plays an important role in scar hyperplasia. These findings provide a new mechanism of hypertrophic scar formation and offer new therapeutic targets.


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