Epigenetic‐Modification of Adult Fibroblast Cells into OCT4+ and VEGFR‐2+ Angiogenic Cells

Abstract

RationaleThe epigenome of fibroblast cells is plastic. Here, we address the hypothesis that fibroblast cells can be epigenetically modified into blood vessel forming cells.Methods and ResultsHuman adult dermal fibroblast cells (hADFCs) were treated with optimal concentrations of chromatin‐modifying agents 5‐aza‐2′‐deoxycytidine (5‐Aza) and trichostatin A (TSA), thereafter subjected to activation of canonical Wnt signaling. We provide evidence 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) and Lipid Phosphate Phosphatase‐3 (LPP3). Staining and microscopic analysis showed differential localization of β‐catenin and OCT4 proteins in epigenetically modified hADFCs. Accordingly, in a chromatin immunoprecipitation (ChIP) assay, OCT4 bound to the VEGFR‐2/FLK1 promoter. Finally, these modified hADFCs also transduced Wnt signaling. Importantly, on a three‐dimensional (3D) Matrigel, a subset of modified cells formed branching point network‐like structures in VEGF‐dependent manner.SummaryThe epigenome of adult fibroblast cells is amenable to epigenetic modification, and has significant implications for the use of epigenetically modified cells to promote angiogenesis in vivo.Support or Funding InformationStudies were supported by the RO1‐HL079356 and (GRNT25710129) and by the University of Illinois at Chicago Center for Clinical and Translation Science Award (UL1RR029879) to K.K.W. J.B was supported by AHA pre‐doctoral fellowship Mid‐West affiliate (15PRE22760004) and CCTS‐PECTs (1UL1TR002003). The UIC, RRC Core Imaging Facility, at the University of Illinois Chicago.