Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis

• Published in: Stem cell reports 2017-11, Vol.9 (5), p.1573-1587
• Main Authors: Fraineau, Sylvain, Palii, Carmen G., McNeill, Brian, Ritso, Morten, Shelley, William C., Prasain, Nutan, Chu, Alphonse, Vion, Elodie, Rieck, Kristy, Nilufar, Sharmin, Perkins, Theodore J., Rudnicki, Michael A., Allan, David S., Yoder, Mervin C., Suuronen, Erik J., Brand, Marjorie
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; bivalent genes; Cells, Cultured; ECFCs; Endothelial Progenitor Cells - cytology; Endothelial Progenitor Cells - metabolism; Endothelial Progenitor Cells - transplantation; Epigenesis, Genetic; epigenetics; EZH2; Female; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hindlimb - blood supply; hindlimb ischemia; human endothelial progenitors; Humans; Ischemia - therapy; Mice; Mice, Inbred NOD; Mice, SCID; Neovascularization, Physiologic; pro-angiogenic pathway; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Receptors, Vascular Endothelial Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor - metabolism; Signal Transduction; Stem Cell Transplantation; UTX; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; vasculogenesis; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.09.009

Human endothelial colony-forming cells (ECFCs) represent a promising source of adult stem cells for vascular repair, yet their regenerative capacity is limited. Here, we set out to understand the molecular mechanism restricting the repair function of ECFCs. We found that key pro-angiogenic pathways are repressed in ECFCs due to the presence of bivalent (H3K27me3/H3K4me3) epigenetic marks, which decreases the cells' regenerative potential. Importantly, ex vivo treatment with a combination of epigenetic drugs that resolves bivalent marks toward the transcriptionally active H3K4me3 state leads to the simultaneous activation of multiple pro-angiogenic signaling pathways (VEGFR, CXCR4, WNT, NOTCH, SHH). This in turn results in improved capacity of ECFCs to form capillary-like networks in vitro and in vivo. Furthermore, restoration of perfusion is accelerated upon transplantation of drug-treated ECFCs in a model of hindlimb ischemia. Thus, ex vivo treatment with epigenetic drugs increases the vascular repair properties of ECFCs through transient activation of pro-angiogenic signaling pathways. [Display omitted] •Pro-angiogenic pathways are maintained in a poised state in ECFCs•Epigenetic drugs resolve bivalently marked genes toward an active state in ECFCs•Treatment with epigenetic drugs activates multiple pro-angiogenic pathways in ECFCs•Ex vivo treatment with epigenetic drugs increases ECFC-mediated vasculogenesis Endothelial colony-forming cells (ECFCs) have the unique capability to form blood vessels in vivo. Here, Brand and colleagues show that the regenerative function of ECFCs is restricted by the presence of bivalent histone marks on pro-angiogenic genes. This poised status can be overcome through the combined action of epigenetic drugs that simultaneously activate multiple pro-angiogenic pathways to increase ECFC-mediated vasculogenesis.