Abstract
We developed a novel mouse model of human refractory cutaneous ulcers that more faithfully reflects pathology and evaluated the effects of mixed cell sheets comprising peripheral blood mononuclear cells and fibroblasts, which we previously developed for treating refractory cutaneous ulcers. Model development involved sandwiching the skin between two magnets, one of which was implanted under the skin for 7 consecutive days. This magnet-implanted ulcer model produced persistently large amounts of exudate and induced the infiltration of the ulcer with inflammatory cells. The model mice had a thicker epidermis and impaired transforming growth factor-β (TGF-β) signaling followed by SMAD2 down-regulation, which causes epidermal hyperplasia in chronic ulcers. Impaired TGF-β signaling also occurred in the ulcers of critical limb ischemia patients. Mixed cell implantation in this ulcer model reduced TNF-α and IL-6 levels in the tissues surrounding the mixed cell sheet-treated ulcers compared with controls or mice treated with trafermin (FGF2). Seven days after commencing therapy, the epidermis was thinner in mice treated with the mixed cell sheets than in controls. This model may therefore serve as a clinically relevant model of human ulcers, and our mixed cell sheets may effectively relieve chronic inflammation and inhibit refractoriness mechanisms.
Highlights
Wound healing is a highly regulated, complex process requiring an appropriate influx of inflammatory cells, granulation tissue that forms a network of capillaries induced by angiogenesis, fibroblast migration, fibroblast conversion to myofibroblasts, collagen deposition, and re-epithelialization
We developed a novel mouse model of ulcers relevant to refractory cutaneous ulcers in humans
Magnet-implanted ulcers showed persistent and larger amounts of exudates than ulcers formed by introducing a simple skin defect, and numerous immature vessels and inflammatory cells were observed in ulcers formed by implanted magnets
Summary
Wound healing is a highly regulated, complex process requiring an appropriate influx of inflammatory cells, granulation tissue that forms a network of capillaries induced by angiogenesis, fibroblast migration, fibroblast conversion to myofibroblasts, collagen deposition, and re-epithelialization. It is difficult to develop suitable animal models of refractory skin ulcers, limiting new therapy development. Animal models of ulcers[2, 9] are developed as follows: simple excision, cutaneous ischemia and reperfusion injury caused by intermittent skin sandwiching between magnets[10, 11], ischemia induced by a skin flap or supplemental vessel ligation[12, 13], diabetic mice[14], and infected wounds[15]. Because of the unique panniculus carnosus layer of mouse skin, which promotes rapid wound contraction[9], no model exhibits a dramatic delay in wound closure that reflects the clinical manifestation. We focused on the molecular environment in the wound to reproduce an actual human refractory skin ulcer than on the wound closure speed to develop a mouse model of cutaneous ulcers
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