Chromatin-modifying agents convert fibroblasts to OCT4+ and VEGFR-2+ capillary tube-forming cells

Abstract

RationaleThe human epigenome is plastic. The goal of this study was to address if fibroblast cells can be epigenetically modified to promote neovessel formation.Methods and resultsHere, we used highly abundant human adult dermal fibroblast cells (hADFCs) that were treated with the chromatin-modifying agents 5-aza-2'-deoxycytidine and trichostatin A, and subsequently subjected to differentiation by activating Wnt signaling. Our results show that these epigenetically modified hADFCs increasingly expressed β-catenin, pluripotency factor octamer-binding transcription factor-4 (OCT4, also known as POU5F1), and endothelial cell (EC) marker called vascular endothelial growth factor receptor-2 (VEGFR-2, also known as Fetal Liver Kinase-1). In microscopic analysis, β-catenin localized to cell-cell contact points, while OCT4 was found to be localized primarily to the nucleus of these cells. Furthermore, in a chromatin immunoprecipitation experiment, OCT4 bound to the VEGFR-2/FLK1 promoter. Finally, these modified hADFCs also transduced Wnt signaling. Importantly, on a two-dimensional (2D) gel substrate, a subset of the converted cells formed vascular network-like structures in the presence of VEGF.ConclusionChromatin-modifying agents converted hADFCs to OCT4+ and VEGFR-2+ capillary tube-forming cells in a 2D matrix in VEGF-dependent manner.

YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT

“…Cardiac fibroblasts were once thought to be terminally differentiated cells. However, recent studies have shown that chromatin-modifying agents could activate Wnt signaling to transform human adult dermal fibroblast cells to OCT4+ and VEGFR-2+ capillary tube-forming cells [3]. When pathological damage occurs in the heart, fibroblasts undergo a mesenchymal-endothelial transition (MEndoT) to obtain endothelial cell-like functions and participate in angiogenesis in the cardiac injury area, which is a novel antifibrotic strategy to alleviate myocardial fibrosis [4].…”

Bioactive Molecules for Skin Repair and Regeneration: Progress and Perspectives

“…5-Aza-2 ′ -deoxycytidine, a DNA methyltransferase inhibitor, and trichostatin A, a histone deacetylase inhibitor, may cause chromatin decondensation and induce a short "dedifferentiation" state. Tideglusib inhibited β-catenin phosphorylation, which resulted in its translocation to the nucleus activation of Wnt signaling, thus causing the differentiation [73]. These results illustrate the feasibility of direct reprogramming for obtaining endothelial cells by bioactive molecule induction, but more achievable paths and the critical signaling pathways for reprogramming need to be further explored.…”