Tumor Necrosis Factor-α-Activated Human Adipose Tissue-Derived Mesenchymal Stem Cells Accelerate Cutaneous Wound Healing through Paracrine Mechanisms

Human adipose tissue-derived mesenchymal stem cells (ASCs) stimulate regeneration of injured tissues by secretion of various cytokines and chemokines. Wound healing is mediated by multiple steps including inflammation, epithelialization, neoangiogenesis, and proliferation. To explore the paracrine functions of ASCs on regeneration of injured tissues, cells were treated with tumor necrosis factor-alpha (TNF-alpha), a key inflammatory cytokine, and the effects of TNF-alpha-conditioned medium (CM) on tissue regeneration were determined using a rat excisional wound model. We demonstrated that TNF-alpha CM accelerated wound closure, angiogenesis, proliferation, and infiltration of immune cells into the cutaneous wound in vivo. To assess the role of proinflammatory cytokines IL-6 and IL-8, which are included in TNF-alpha CM, IL-6 and IL-8 were depleted from TNF-alpha CM using immunoprecipitation. Depletion of IL-6 or IL-8 largely attenuated TNF-alpha CM-stimulated wound closure, angiogenesis, proliferation, and infiltration of immune cells. These results suggest that TNF-alpha-activated ASCs accelerate cutaneous wound healing through paracrine mechanisms involving IL-6 and IL-8.