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Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes.

  • Zheng X Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; xiaowei.zheng@ki.se Sergiu-Bogdan.Catrina@ki.se.
  • Narayanan S Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Sunkari VG Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Eliasson S Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Botusan IR Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Grünler J Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Catrina AI Department of Rheumatology, Karolinska University Hospital Solna, 17176 Stockholm, Sweden.
  • Radtke F Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, 1015 Lausanne, Switzerland.
  • Xu C Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Zhao A Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Ekberg NR Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Lendahl U Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden.
  • Catrina SB Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden; xiaowei.zheng@ki.se Sergiu-Bogdan.Catrina@ki.se.
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  • 2019-03-20
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2019
Dll4
Notch1
diabetes
diabetic foot ulcer
wound healing
Aged
Animals
Calcium-Binding Proteins
Diabetes Mellitus, Experimental
Diabetic Foot
Female
Humans
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Keratinocytes
Male
Membrane Proteins
Mice
Receptor, Notch1
Signal Transduction
Wound Healing
English 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)-Notch1 feedback 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/209930
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