MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing

Uchiyama, Akihiko; Yamada, Kazuya; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yûkô; Udey, Mark C.; Ishikawa, Osamu; Motegi, Sei‐ichiro

doi:10.1016/j.ajpath.2014.03.017

Cited by 71 publications

(72 citation statements)

References 36 publications

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“…We recently demonstrated that MFG-E8 regulates angiogenesis and wound healing in a cutaneous wound healing mice model (Uchiyama et al, 2014). In the present study using a murine I/R model, we additionally determined that MFG-E8 regulates the functions of M1 macrophages, including the secretion of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 96%

“…We previously determined that pericytes were the major sources of MFG-E8 in B16 melanoma tumors, and that MFG-E8 localized in close proximity to pericytes/vascular SMCs in the dermis of murine and human skin (Motegi et al, 2011a;Uchiyama et al, 2014). In addition, immunofluorescence staining of skin in the I/R site showed that the MFG-E8 expression levels around blood vessels were enhanced during ischemia.…”

Section: Expression Of Mfg-e8 In Pericyte-like Cells Endothelial Celmentioning

confidence: 97%

“…We have also determined that MFG-E8 associated with integrin av and platelet-derived growth factor receptor b (PDGFRb) on the surface of pericytes after platelet-derived growth factor (PDGF) treatment, and inhibited PDGF-stimulated degradation of PDGFRb, resulting in the enhancement of PDGFRb signaling mediated by integrin-growth factor receptor cross talk (Motegi et al, 2011b). Moreover, we recently demonstrated that MFG-E8 is important for cutaneous wound healing using a mouse model with full-thickness cutaneous wounds (Uchiyama et al, 2014), in which MFG-E8 was increased in granulation tissue in cutaneous wound area. Wound healing was significantly delayed in MFG-E8 knockout (KO) mice compared with wildtype (WT) mice, and recombinant mouse MFG-E8 (rMFG-E8) treatment enhanced wound healing in MFG-E8 KO mice.…”

Section: Introductionmentioning

confidence: 96%

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Protective Effect of MFG-E8 after Cutaneous Ischemia–Reperfusion Injury

Uchiyama

Yamada

Perera

et al. 2015

Journal of Investigative Dermatology

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We recently demonstrated that the secreted glycoprotein and integrin-ligand MFG-E8 promotes cutaneous wound healing by enhancing angiogenesis. Several studies have identified potential roles for MFG-E8 in regulation of ischemia-reperfusion (I/R) injury in the brain, kidney, and liver. Our objective was to assess the role of MFG-E8 in the formation of skin ulcers using a murine model of cutaneous I/R injury-cutaneous pressure ulcers. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 hours, followed by plate removal. Expression of MFG-E8 increased in the dermis during ischemia, and then decreased after reperfusion. Administration of recombinant (r)MFG-E8 in I/R areas at the beginning of reperfusion significantly inhibited the formation of cutaneous pressure ulcers, and the number of CD31(+) vessel and NG2(+) pericytes in wounds were increased in I/R mice treated with rMFG-E8. The number of M1 macrophages and the amount of proinflammatory mediators monocyte chemotactic protein-1,induced nitric oxide synthase, IL-6, tumor necrosis factor-α, and IL-1β in the wound area were reduced by the administration of rMFG-E8. We conclude that MFG-E8 may inhibit the formation of pressure ulcers induced by cutaneous I/R injury by regulating angiogenesis and inflammation. Exogenous application of MFG-E8 might have therapeutic potential for cutaneous I/R injuries, including decubitus ulcers and Raynaud's phenomenon-induced digital ulcers.

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Section: Discussionmentioning

confidence: 96%

Section: Expression Of Mfg-e8 In Pericyte-like Cells Endothelial Celmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 96%

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Protective Effect of MFG-E8 after Cutaneous Ischemia–Reperfusion Injury

Uchiyama

Yamada

Perera

et al. 2015

Journal of Investigative Dermatology

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“…The carboxy-terminal domains of MFG-E8 can bind to negatively charged phospholipids (20), resulting in the opsonization of apoptotic cells for uptake by phagocytes (19, 21). In addition, interactions between MFG-E8 and integrin αv have been implicated in the enhancement of angiogenesis in mice (22-24). …”

Section: Introductionmentioning

confidence: 99%

MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell–Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages

et al. 2016

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Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MGF-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas which express it. We found that mouse bone marrow-derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type we implanted melanoma cells and MSC derived from wild-type (WT) or MFG-E8-deficient (KO) into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects co-implanted with KO-MSC compared to WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays we confirmed that WT-MSC-conditioned medium was more potent at inducing M2 macrophage polarization, compared to KO-MSC-conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis.

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“…Furthermore, evidence has suggested that MFG-E8 protects against acute inflammatory injury in numerous organs such as lung, brain, and intestines [Ajakaiye et al, 2012; Aziz et al, 2012; Cheyuo et al, 2012]. Recently, MFG-E8 has been found to regulate osteoclast homeostasis and inflammatory bone loss as well as angiogenesis in cutaneous wound healing [Abe et al, 2014; Uchiyama et al, 2014]. It inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury [Deroide et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms Underlying the Regulation of the MFG‐E8 Gene Promoter Activity in Physiological and Inflammatory Conditions

Wang

Liu

et al. 2015

J of Cellular Biochemistry

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Milk fat globule-EGF factor 8 (MFG-E8) is expressed by macrophages and plays an important role in attenuating inflammation and maintaining tissue homeostasis. Previously, we and others found that LPS inhibits MFG-E8 gene expression in macrophages. Here, we characterized the 5′-flanking region of the mouse MFG-E8 gene. To functionally analyze the upstream regulatory region of the MFG-E8 gene, a series of luciferase reporter gene constructs containing deleted or mutated regulatory elements were prepared. Using the luciferase assay, we revealed that Sp1 binding motifs within the proximal promoter region were necessary for full activity of the MFG-E8 promoter, whereas AP-1 like binding sequence at −372 played a role in governing the promoter activity at a homeostatic level. With chromatin immunoprecipitation assay, we showed that Sp1 and c-Jun physically interact with the MFG-E8 promoter region in vivo. In addition, Sp1 was found to regulate the MFG-E8 promoter activity positively and c-Jun negatively. Furthermore, we demonstrated that LPS inhibited MFG-E8 promoter activity via targeting Sp1 and AP-1-like motifs in the 5′-flanking region. Collectively, our data indicate that Sp1 and AP-1-related factors are involved in the regulation of MFG-E8 gene transcription by targeting their binding sites in the 5′-flanking region under physiological and inflammatory states.

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MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing

Cited by 71 publications

References 36 publications

Protective Effect of MFG-E8 after Cutaneous Ischemia–Reperfusion Injury

Protective Effect of MFG-E8 after Cutaneous Ischemia–Reperfusion Injury

MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell–Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages

Molecular Mechanisms Underlying the Regulation of the MFG‐E8 Gene Promoter Activity in Physiological and Inflammatory Conditions

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