title: Mast Cells Regulate Wound Healing in Diabetes.
abstract: Diabetic foot ulceration is a severe complication of diabetes that lacks effective treatment. Mast cells (MCs) contribute to wound healing, but their role in diabetes skin complications is poorly understood. Here we show that the number of degranulated MCs is increased in unwounded forearm and foot skin of patients with diabetes and in unwounded dorsal skin of diabetic mice (P < 0.05). Conversely, postwounding MC degranulation increases in nondiabetic mice, but not in diabetic mice. Pretreatment with the MC degranulation inhibitor disodium cromoglycate rescues diabetes-associated wound-healing impairment in mice and shifts macrophages to the regenerative M2 phenotype (P < 0.05). Nevertheless, nondiabetic and diabetic mice deficient in MCs have delayed wound healing compared with their wild-type (WT) controls, implying that some MC mediator is needed for proper healing. MCs are a major source of vascular endothelial growth factor (VEGF) in mouse skin, but the level of VEGF is reduced in diabetic mouse skin, and its release from human MCs is reduced in hyperglycemic conditions. Topical treatment with the MC trigger substance P does not affect wound healing in MC-deficient mice, but improves it in WT mice. In conclusion, the presence of nondegranulated MCs in unwounded skin is required for proper wound healing, and therapies inhibiting MC degranulation could improve wound healing in diabetes.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Tellechea
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ermelindo C
authors.initials: EC
authors.lastname: Leal
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Antonios
authors.initials: A
authors.lastname: Kafanas
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Auster
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Sarada
authors.initials: S
authors.lastname: Kuchibhotla
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Ostrovsky
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tecilazich
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Baltzis
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Eugénia
authors.initials: E
authors.lastname: Carvalho
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Zabolotny
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Petra
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.
authors.forename: Arti
authors.initials: A
authors.lastname: Patel
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.
authors.forename: Smaro
authors.initials: S
authors.lastname: Panagiotidou
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Leena
authors.initials: L
authors.lastname: Pradhan-Nabzdyk
authors.affiliation: Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA.
authors.forename: Theoharis C
authors.initials: TC
authors.lastname: Theoharides
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA aveves@bidmc.harvard.edu.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
mesh_terms: D000368:Aged; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000502:physiology*