Interleukin 11 drives dermal fibroblast activation in mechanical stretch-mediated skin expansion

In plastic and reconstructive surgery, mechanical stretch (MS) forces are frequently used to stimulate skin regeneration in order to produce additional skin for repairing tissue defects. Fibroblast activation in response to MS is crucial for skin growth during skin expansion. While its function in skin expansion is unknown, interleukin 11 (IL11) has been described as a cytokine that is increased in response to mechanical stimuli. In this study, we demonstrated that the expression of IL11 and IL11 receptor alpha subunit (IL11RA) was significantly increased in dermal fibroblasts (DFs) of the well-regenerated expanded skins (ESs) in human and mouse samples. However, IL11 was relatively lacking in the poorly-regenerated human ESs. Through the inhibition of IL11 signaling, MS-induced fibroblast proliferation, extracellular matrix (ECM) production, and myofibroblast activation were all inhibited in vitro. Consistently, depletion of IL11 signaling in vivo reduced skin regeneration during skin expansion, as evidenced by decreased dermal thickness and inhibited fibroblast function. Notably, transcriptomic analysis revealed that MS stimulation induced the upregulation of pathways associated with cell proliferation, collagen synthesis, stress response, and cell activation, whereas these pathways were downregulated in the IL11RA knockdown group. Mechanistically, we discovered that WNT5B acts as a downstream regulator of IL11-mediated cell activation in the presence of MS. Finally, the administration of recombinant IL11 via intradermal injection into mice significantly promoted fibroblast activation and halted the reduction in dermal thickness that occurred during skin expansion. In summary, our study demonstrated that IL11 signaling plays a crucial role in the activation of fibroblasts induced by MS, making it a promising target for clinical application in enhancing skin regeneration during skin expansion.