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

Abstract

SummaryHuman 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.

Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina

“…We selected the promoters of genes regulated by the PRC2-regulated factor GATA2, which promotes expression of genes of endothelialspecific identity and function (e.g., CD31, vWF, endothelin-1, and ICAM2). We also selected promoters of genes known to be activated by chemical EZH2 and histone deacetylase (HDAC) derepression in human endothelial progenitor cells (EPC) (e.g., CXCR4, DLL1, and FZD7) 44 . CD31 + CD146 + DVPs vs. N-DVP were MACS-purified, briefly expanded in EGM2, and ChIP-qPCR was performed on promoter sites of these genes.…”

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…It has been postulated that epigenetic drugs might derepress crucial proangiogenic signaling pathways, thereby improving ECFC’s vasculogenic ability in vivo ( Table 6 ) [ 207 , 208 , 209 ]. For instance, ex vivo pre-treatment with trichostatin, a histone deacetylase (HDAC) inhibitor, enhanced ECFCs-mediated revascularization and blood flow recovery in a murine model of hindlimb ischemia [ 210 ].…”

Endothelial Colony‐Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease

“…Alternatively, one can also postulate that epigenetic changes could result from perinatal stressors associated with very preterm birth and may contribute to the establishment of ECFC dysfunction. Key pro‐angiogenic pathways including vascular endothelial growth factor receptors and Notch expression in ECFC are susceptible to epigenetic histone modifications, which were shown to remarkably blunt in vitro ECFC vasculogenic capacity 59, 60. Together, our current study and others suggest that the function of adult EPCs, particularly ECFCs, may be determined by perinatal factors; however, the mechanisms by which such ECFC dysfunction can persist beyond birth and into adulthood remain to be studied.…”