title: Correction of MFG-E8 Resolves Inflammation and Promotes Cutaneous Wound Healing in Diabetes.
abstract: Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a peripheral glycoprotein that acts as a bridging molecule between the macrophage and apoptotic cells, thus executing a pivotal role in the scavenging of apoptotic cells from affected tissue. We have previously reported that apoptotic cell clearance activity or efferocytosis is compromised in diabetic wound macrophages. In this work, we test the hypothesis that MFG-E8 helps resolve inflammation, supports angiogenesis, and accelerates wound closure. MFG-E8(-/-) mice displayed impaired efferocytosis associated with exaggerated inflammatory response, poor angiogenesis, and wound closure. Wound macrophage-derived MFG-E8 was recognized as a critical driver of wound angiogenesis. Transplantation of MFG-E8(-/-) bone marrow to MFG-E8(+/+) mice resulted in impaired wound closure and compromised wound vascularization. In contrast, MFG-E8(-/-) mice that received wild-type bone marrow showed improved wound closure and improved wound vascularization. Hyperglycemia and exposure to advanced glycated end products inactivated MFG-E8, recognizing a key mechanism that complicates diabetic wound healing. Diabetic db/db mice suffered from impaired efferocytosis accompanied with persistent inflammation and slow wound closure. Topical recombinant MFG-E8 induced resolution of wound inflammation, improvements in angiogenesis, and acceleration of closure, upholding the potential of MFG-E8-directed therapeutics in diabetic wound care.
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Amitava
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Subhadip
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Mithun
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Scott
authors.initials: S
authors.lastname: Chaffee
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Noha S
authors.initials: NS
authors.lastname: Ahmed
authors.affiliation: Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH 43210; and.
authors.forename: Narasimham L
authors.initials: NL
authors.lastname: Parinandi
authors.affiliation: Division of Biosciences, The Ohio State University, Columbus, OH 43210.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Division of Biosciences, The Ohio State University, Columbus, OH 43210.
authors.forename: John F
authors.identifier: 0000-0002-6927-0266
authors.initials: JF
authors.lastname: Sheridan
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.affiliation: Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH 43210; Davis Heart and Lung Research Institute, Ohio State University Wexner Medical Center, Columbus, OH 43210; Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, Ohio State University Wexner Medical Center, Columbus, OH 43210; sashwati.roy@osumc.edu.
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
mesh_terms: D042501:Angiogenic Proteins / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D003920:Diabetes Mellitus / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D010587:Phagocytosis; D014945:Wound Healing
chemical_list: D042501:Angiogenic Proteins; D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins