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(American Journal of Pathology. 2005;167:1519-1529.)
© 2005 American Society for Investigative Pathology

Tissue Regeneration Using Macrophage Migration Inhibitory Factor-Impregnated Gelatin Microbeads in Cutaneous Wounds

Yunan Zhao*, Tadamichi Shimizu*, Jun Nishihira{dagger}, Yoshikazu Koyama{ddagger}, Toshihiro Kushibiki§, Ayumi Honda*, Hirokazu Watanabe*, Riichiro Abe*, Yasuhiko Tabata§ and Hiroshi Shimizu*

From the Departments of Dermatology* and Biochemistry,{dagger} Hokkaido University Graduate School of Medicine, Sapporo; Genetic Laboratory,{ddagger} Sapporo; and the Institute for Frontier Medical Science,§ Kyoto University, Kyoto, Japan

Migration inhibitory factor (MIF) responds to tissue damage and regulates inflammatory and immunological processes. To elucidate the function of MIF in cutaneous wound healing, we analyzed MIF knockout (KO) mice. After the excision of wounds from the dorsal skin of MIF KO and wild-type (WT) mice, healing was significantly delayed in MIF KO mice compared to WT mice. Lipopolysaccharide treatment significantly increased [3H]thymidine uptake in WT mouse fibroblasts compared to MIF KO mouse fibroblasts. Furthermore, there was a significant reduction in fibroblast and keratinocyte migration observed in MIF KO mice after 1-oleoyl-2-lysophosphatidic acid treatment. We subsequently examined whether MIF-impregnated gelatin slow-release microbeads could accelerate skin wound healing. Injection of more than 1.5 µg/500 µl of MIF-impregnated gelatin microbeads around a wound edge accelerated wound healing compared to a single MIF injection without the use of microbeads. MIF-impregnated gelatin microbeads also accelerated skin wound healing in C57BL/6 mice and diabetic db/db mice. Furthermore, incorporating MIF-impregnated gelatin microbeads into an artificial dermis implanted into MIF KO mice accelerated procollagen production and capillary formation. These findings suggest that MIF is crucial in accelerating cutaneous wound healing and that MIF-impregnated gelatin microbeads represent a promising treatment to facilitate skin wound healing.






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Copyright © 2005 by the American Society for Investigative Pathology.