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Epithelial To Mesenchymal Transition Mediator Zeb1 Controls Wound Epithelialization And Angiogenesis In A Glycemic Status Dependent Manner
Kanhaiya Singh, Mithun Sinha, Durba Pal, Dolly Khona, Saba Tabasum, Savita Khanna, Sashwati Roy, Chandan K Sen
University
2019-02-15
Presenter: kanhaiya singh
Affidavit:
I certify that the material proposed for presentation in this abstract has not been published in any scientific journal or previously presented at a major meeting.
Director Name: CKS
Author Category: Other Specialty Resident
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
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 causes EMT. Additionally, ZEB1 stimulates angiogenesis acting as an endothelial cell survival factor. 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. Cutaneous wounding resulted in loss of epithelial marker E-cadherin with concomitant gain of ZEB1. 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. Under hyperglycemic conditions, ZEB1 was induced by two orders of magnitude. Furthermore, ChIP assay showed that under such conditions ZEB1 lost its ability to bind E-cadherin. 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. This work recognizes ZEB1 as a critical determinant of normal and diabetic wound angiogenesis and closure.
