Mast Cells Regulate Wound Healing in Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 7; pp. 2006 - 2019
• Main Authors: Tellechea, Ana, Leal, Ermelindo C, Kafanas, Antonios, Auster, Michael E, Kuchibhotla, Sarada, Ostrovsky, Yana, Tecilazich, Francesco, Baltzis, Dimitrios, Zheng, Yongjun, Carvalho, Eugénia, Zabolotny, Janice M, Weng, Zuyi, Petra, Anastasia, Patel, Arti, Panagiotidou, Smaro, Pradhan-Nabzdyk, Leena, Theoharides, Theoharis C, Veves, Aristidis
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2016
• Subjects: Aged; Animals; Cells; Complications; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - pathology; Female; Humans; Male; Mast Cells - metabolism; Mast Cells - pathology; Mice; Middle Aged; Pressure ulcers; Skin - metabolism; Skin - pathology; Vascular endothelial growth factor; Wound healing; Wound Healing - physiology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-0340

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.