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DKK3 (Dikkopf-3) Transdifferentiates Fibroblasts Into Functional Endothelial Cells-Brief Report

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Ting Chen, Eirini Karamariti, Xuechong Hong, Jiacheng Deng, Yutao Wu, Wenduo Gu, Russell Simpson, Mei Mei Wong, Baoqi Yu, Yanhua Hu, Aijuan Qu, Qingbo Xu, Li Zhang

Original languageEnglish
Pages (from-to)765-773
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume39
Issue number4
DOIs
Accepted/In press8 Feb 2019
Published1 Apr 2019

King's Authors

Abstract

Objective- To determine the role of a cytokine-like protein DKK3 (dikkopf-3) in directly transdifferentiating fibroblasts into endothelial cells (ECs) and the underlying mechanisms. Approach and Results- DKK3 overexpression in human fibroblasts under defined conditions for 4 days led to a notable change in cell morphology and progenitor gene expression. It was revealed that these cells went through mesenchymal-to-epithelial transition and subsequently expressed KDR (kinase insert domain receptor) at high levels. Further culture in EC defined media led to differentiation of these progenitors into functional ECs capable of angiogenesis both in vitro and in vivo, which was regulated by the VEGF (vascular endothelial growth factor)/miR (microRNA)-125a-5p/Stat3 (signal transducer and activator of transcription factor 3) axis. More importantly, fibroblast-derived ECs showed the ability to form a patent endothelium-like monolayer in tissue-engineered vascular grafts ex vivo. Conclusions- These data demonstrate that DKK3 is capable of directly differentiating human fibroblasts to functional ECs under defined media and provides a novel potential strategy for endothelial regeneration.

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