Mechanical stretch-induced IGF2 overexpression in epidermal keratinocytes promotes hypertrophic scar formation through the IGF1R/p-c-Jun axis.

Insulin-like growth factor 2 (IGF2) is a mitogenic peptide hormone expressed by various tissues. Although it is three times more abundant in serum than IGF1, its physiological and pathological roles are yet to be fully understood. Previous transcriptome sequencing studies have shown that IGF2 expression is increased in hypertrophic scar (HS); however, its role in HS formation and the underlying mechanism remains elusive. The present study found that IGF2 expression was significantly higher in HS than in normal skin (NS), particularly in epidermal cells. Moreover, mechanical stretch increased IGF2 expression and secretion in keratinocytes, affecting the biological activities of fibroblasts, including proliferation, migration, and collagen synthesis, and transdifferentiated into myofibroblasts after co-culturing keratinocytes with fibroblasts. Mechanistically, keratinocyte-secreted IGF2 activated a nuclear transcription factor phosphorylated c-Jun (p-c-Jun) through insulin-like growth factor 1 receptor (IGF1R) on fibroblast cytomembrane, thereby triggering the profibrotic effect of IGF2. Blocking IGF1R or p-c-Jun inhibited the IGF2-induced profibrotic effect of fibroblasts. Moreover, increased p-c-Jun expression restored the reduction in fibrosis induced by IGF1R knockdown. The IGF2 recombinant protein was also applied to a mouse wound-healing scar model. It was found that IGF2 significantly promoted the formation of HS, whereas IGF2 small molecule inhibitor chromeceptin inhibited HS formation. In conclusion, this study demonstrates that mechanical stretch-induced IGF2 overexpression in epidermal keratinocytes promotes fibroblast activation through the IGF1R/p-c-Jun axis. Therefore, IGF2 may act as a therapeutic target for HS.