TNF-α-Activated Adipose–Derived Stem Cells Producing IL-8 Through the TNF-α/NF-κB Signaling Pathway to Improve the Quality of Full-Thickness Skin Grafts

Abstract

Abstract Skin grafting has the disadvantages of high contracture rate and poor texture. Adipose-derived stem cells (ADSCs) therapy is a promising “therapeutic angiogenesis” approach; however, safety and low treatment efficiency of direct injection into defects have limited its use. Herein, we first used TNF-α to activate ADSCs, and then used TNF-α-activated ADSCs (t-ADSCs) to promote angiogenesis in donor skin. Finally, the use of pretreated donor skin for grafting can reduce the contracture rate and improve skin texture. In vitro, cell proliferation, migration, and pro-angiogenic abilities were tested to measure the cell function of t-ADSCs. The signaling pathway and paracrine cytokine related to the pro-angiogenic effect of t-ADSCs were screened out and validated. In vivo, t-ADSCs were first injected intradermally into the donor skin of full-thickness skin grafts (FTSGs). Next, the level of angiogenesis in donor skin was evaluated. Finally, the pretreated donor skin was used for grafting. We found that TNF-α may activate ADSCs through the TNF-α/NF-κB pathway and enhance the paracrine ability of the angiogenic factor interleukin-8 (IL-8), ultimately promoting the angiogenesis of the donor skin. The use of vasculature-rich donor skin for grafting could accelerate skin graft anastomosis; shorten the nutrient deprivation time of the epidermis, dermis and hair follicles; and thereby improve the quality of FTSGs. This study demonstrated a possible mechanism through which TNF-α acts on ADSCs to improve their angiogenic capacity and provide a novel approach for the repair of skin and soft tissue wounds.