Wound Healing Society

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Epithelial To Mesenchymal Transition Mediator Zeb1 Controls Wound Epithelialization And Angiogenesis In A Glycemic Status Dependent Manner
Kanhaiya Singh1, Mithun Sinha1, Durba Pal2, Dolly Khona1, Saba Tabasum1, Surya Gnyawali2, Fidel Soto-Gonzalez2, Savita Khanna1, Sashwati Roy1, Chandan K. Sen1.
1Indiana University School of Medicine, Indianapolis, IN, USA, 2The Ohio State University, Columbus, OH, USA.

Background: Efficient wound healing process require a tight interplay between factors governing epithelial to mesenchymal transition (EMT) and wound vascularization. Zinc finger E-box binding homeobox 1 (ZEB1), primarily studied in the context of tumor biology, is a potent EMT-activator. ZEB1 is a transcriptional repressor of epithelial genes like E-cadherin, loss of which cause EMT. Additionally, ZEB1 stimulates angiogenesis via induction of VEGF-A and acting as an endothelial cell survival factor.Methods: Quantitative Stable Isotope Labeling by Amino acids in Cell culture (SILAC) analysis was used to elucidate the ripple effect of ZEB1 overexpression on epithelial cell proteome. Role of ZEB1 in dermal wounds in vivo was assessed using Zeb1 heterozygous Zeb1+/- mice as homozygous Zeb1-/- mice are not viable. Additionally, diabetic wounds were also studied to test ZEB1 and its potential role in compromised healing. Chromatin immunoprecipitation (ChIP) assay and Immunoprecipitation-Mass Spectrometry were done to investigate the differential binding activity of ZEB1 to its target molecules under normoglycemic and hyperglycemic conditions. Results: Cutaneous wounding resulted in loss of epithelial marker E-cadherin with concomitant gain of ZEB1 (n=3,p<0.05). SILAC analyses revealed that the dominant proteins downregulated post ZEB1 overexpression belong to adherens junction pathways. Zeb-1+/- mice exhibited compromised wound closure due to defective EMT and angiogenic response (n=3,p<0.05). Under hyperglycemic conditions, as noted in 12 week old db/db mice, ZEB1 was induced by two orders of magnitude in the skin(n =3,p<0.05). Furthermore, under such conditions ZEB1 lost its ability to bind E-cadherin (n= 3,p<0.05). Keratinocyte E-cadherin, thus upregulated, resisted EMT required for wound healing. Extraordinarily high ZEB1, under diabetic conditions, compromised wound angiogenesis by diminishing VEGF-A mediated signaling. Diabetic wound healing was improved in ZEB+/- mice recognizing ZEB1 as a novel therapeutic target.Conclusion: This work recognizes ZEB1 as a critical determinant of normal and diabetic wound angiogenesis and closure.

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