期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 14, 页码 6985-6994出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1900351116
关键词
diabetic foot ulcer; Notch1; Dll4; wound healing; diabetes
资金
- Swedish Research Council
- Family Erling-Persson Foundation
- Stockholm County Research Council
- Stockholm Regional Research Foundation (ALF)
- Bert von Kantzows Foundation
- Swedish Society of Medicine
- Karolinska Institute's Research Foundations
- Integrated CardioMetabolic Center
- Swedish Cancer Society
- Strategic Research Programme in Diabetes
- Strategic Research Programme in Stem Cells/Regenerative Medicine
Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1-4) and ligands (Jagged 1-2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)-Notch 1feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs.
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