Stem Cell Reports
Volume 9, Issue 5, 14 November 2017, Pages 1573-1587
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Article
Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis

https://doi.org/10.1016/j.stemcr.2017.09.009Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

pro-angiogenic pathway
ECFCs
epigenetics
bivalent genes
human endothelial progenitors
vasculogenesis
angiogenesis
hindlimb ischemia
EZH2
UTX

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Present address: Normandie Université, UNIROUEN, INSERM U1096, 76000 Rouen, France