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

被引：85

作者：

Zheng, Xiaowei ^{[1
,2
]}

Narayanan, Sampath ^{[1
,2
]}

Sunkari, Vivekananda Gupta ^{[1
,7
]}

Eliasson, Sofie ^{[1
,2
]}

Botusan, Ileana Ruxandra ^{[1
,2
]}

Grunler, Jacob ^{[1
,2
]}

Catrina, Anca Irinel ^{[3
]}

Radtke, Freddy ^{[4
]}

Xu, Cheng ^{[1
,2
]}

Zhao, Allan ^{[1
]}

Ekberg, Neda Rajamand ^{[1
,2
]}

Lendahl, Urban ^{[5
]}

Catrina, Sergiu-Bogdan ^{[1
,2
,6
]}

机构：

[1] Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden

[2] Karolinska Univ Hosp, Dept Endocrinol & Diabet, S-17176 Stockholm, Sweden

[3] Karolinska Univ Hosp Solna, Dept Rheumatol, S-17176 Stockholm, Sweden

[4] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, CH-1015 Lausanne, Switzerland

[5] Karolinska Inst, Dept Cell & Mol Biol, S-17165 Stockholm, Sweden

[6] Acad Specialist Ctr, Ctr Diabet, S-11365 Stockholm, Sweden

[7] Stanford Univ, Dept Infect Dis & Geog Med, Palo Alto, CA 94305 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 14期

基金：

瑞典研究理事会;

关键词：

diabetic foot ulcer; Notch1; Dll4; wound healing; diabetes; SIGNAL-TRANSDUCTION; DIFFERENTIAL ROLES; NOTCH; CELLS; ANGIOGENESIS; ACTIVATION; GLUCOSE; GROWTH; FOOT; DLL4;

D O I：

10.1073/pnas.1900351116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：6985 / 6994

页数：10

共 65 条

[51]

Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation [J].