MFG-E8 regulates angiogenesis in cutaneous wound healing.
Our research group recently demonstrated that pericytes are major sources of the secreted glycoprotein and integrin ligand lactadherin (MFG-E8) in B16 melanoma tumors, and that MFG-E8 promotes angiogenesis via enhanced PDGF-PDGFRβ signaling mediated by integrin-growth factor receptor crosstalk. However, sources of MFG-E8 and its possible roles in skin physiology are not well characterized. The objective of this study was to characterize the involvement of MFG-E8 in skin wound healing. In the dermis of normal murine and human skin, accumulations of MFG-E8 were found around CD31(+) blood vessels, and MFG-E8 colocalized with PDGFRβ(+), αSMA(+), and NG2(+) pericytes. MFG-E8 protein and mRNA levels were elevated in the dermis during full-thickness wound healing in mice. MFG-E8 was diffusely present in granulation tissue and was localized around blood vessels. Wound healing was delayed in MFG-E8 knockout mice, compared with the wild type, and myofibroblast and vessel numbers in wound areas were significantly reduced in knockout mice. Inhibition of MFG-E8 production with siRNA attenuated the formation of capillary-like structures in vitro. Expression of MFG-E8 in fibrous human granulation tissue with scant blood vessels was less than that in granulation tissue with many blood vessels. These findings suggest that MFG-E8 promotes cutaneous wound healing by enhancing angiogenesis.
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Akihiko
A
Uchiyama
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Kazuya
K
Yamada
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Sachiko
S
Ogino
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Yoko
Y
Yokoyama
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Yuko
Y
Takeuchi
Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Mark C
MC
Udey
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Osamu
O
Ishikawa
Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan. Electronic address: smotegi@gunma-u.ac.jp.
Sei-ichiro
S
Motegi
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D002460:Cell Line; D020405:Dermis / Q000502:physiology*; D006097:Granulation Tissue / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000166:cytology; D012879:Skin Physiological Phenomena; D014945:Wound Healing
D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins