Basic study on development of combination treatments for curative radiotherapy and surgery using regererative medicine

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Pre-operative cancer radiotherapy frequently prevents the following surgical operation, since effective dose of ionized radiation induces wound complication. The purposes in this study are to clarify causes for the impaired wound healing, and to accelerate the wound healing using animal models.One week after X-ray (30Gy) irradiation to the back of rat, full-thickness skin (2 cm-length) was incised and sutured. Impairment of wound healing was characterized by depilation, continuous inflammation, epidermal desquamation and acanthosis, in addition to absence of granulation tissue and impaired vascularization.When incisional wounds of irradiated and non-irradiated skins were sutured each other as a model of end-to-end implantation, granulation tissues in the non-irradiated region expanded in the irradiated region of the skin. The skin of mouse, whose bone marrow has been replaced with GFP-expressing bone marrow cells, was wounded. In the non-irradiated skin, number of GFP-positive cells in … More creased after wounding, whereas, number of GFP-positive cells decreased in the irradiated skin. These findings suggested that infiltration of bone marrow-derived fibrocytes and/or activation of dermal fibroblasts may be disordered in the irradiated skin.The expression of transforming growth factor-β(TGF-β) increased during wound healing of irradiated skins. So, to interfere with TGF-β signaling, recombinant interferon-γ was subcutaneously injected. Granulation formation by myofibroblasts was found in the region of subepidermal bulla in the irradiated skin. Moreover, the inhibitor of TGF-β receptor kinase accelerated the wound healing by suppressing continuous inflammation and ancanthosis.Next, rat groins were irradiated, and the femoral artery and vein in skin flap were anastomosed with that of recipient rat. The irradiated femoral artery showed pachytic tunica intima, and angeitis.In conclusion, to suppress radiation-induced impairment of wound healing, the treatment to enhance the recruitment of bone marrow derived fibrocytes and vascularization may be effective in addition to the treatment of inhibitors for TGF-β signaling. Less