Heterochromatin Protein 1 Alpha (HP1α: CBX5) is a Key Regulator in Differentiation of Endothelial Progenitor Cells to Endothelial Cells

Abstract

As the ability to control the differentiation of endothelial stem/progenitor cells (EPCs) into vascular endothelial cell lineages could be useful for promoting neovascularization, it is important to obtain a deeper understanding of the epigenetic mechanisms that regulate EPC differentiation and neovascularization. Heterochromatin protein 1a (HP1a) is known to be involved in the epigenetic regulation of gene silencing. However, recent reports demonstrate that HP1a can also activate gene expression during cell differentiation. In this study, microarray analysis revealed that HP1a expression was induced during EPC differentiation and is associated with the expression of outgrowing endothelial cell (OEC)-specific protein markers. To explore the role of HP1a in the differentiation of EPCs to OECs, its expression was knocked-down or overexpressed in differentiating EPCs. Overexpression of HP1a promoted the differentiation and angiogenic activity of EPCs in vitro and in vivo, whereas knockdown of HP1a led to a defect in OEC migration, tube formation, and angiogenic sprouting activity. Gene expression profiling showed increased expression of angiogenic genes, including NOTCH1, cadherin-5, and angiopoietin-like-2, and decreased expression of progenitor cell marker genes, including CD133, CXCR4, and C-KIT, in HP1a-overexpressing EPCs. Also, increased HP1a at an early stage of EPC differentiation may regulate angiogenic gene transcription by interacting with chromatin that modifies epigenetic factors such as the methyl-CpG binding domain, Polycomb group ring finger 2, and DNA methyltransferases. Our findings demonstrate, for the first time, that HP1a plays an important role in the differentiation and angiogenic function of EPCs by regulating endothelial gene expression. STEM CELLS 2015;33:1512-1522

Human Cord Blood‐Derived CD133+/C‐Kit+/Lin− Cells Have Bipotential Ability to Differentiate into Mesenchymal Stem Cells and Outgrowth Endothelial Cells

“…Previous studies report that adult peripheral blood and cord blood CKL− MNCs can give rise to MSCs and OECs [8, 21–26]. Consistently, we found that CLK- MNCs purified from cord blood were able to differentiate into both MSCs and OECs with demonstrable biological in vitro and in vivo function.…”

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…Cellular senescence is a permanent proliferation‐arrest induced by telomere shortening, oncogene activation or aging (Chandra et al., 2015; van Deursen, 2014). This process usually leads to SAHF formation, which consists of some transcriptional silencing markers such as heterochromatin protein 1 (HP1) and H3K9Me3 (Maeng, Kwon, Kim, & Kwon, 2015). When DNA is damaged either by laser or aging, E2Fs (E2F1‐3) target genes, such as CyclinA/E, PCNA, and MCM4, are compacted within the SAHF to prevent cell proliferation, and this process is generally a consequence of retinoblastoma (Rb)‐mediated repression of E2Fs activity (Vernier et al., 2011; Zhao et al., 2015).…”

Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications

“…Heterochromatin protein-1 alpha (HP-1 α ), an epigenetic regulator implicated in gene silencing, has been reported to play an important role in promoting EPC differentiation in vitro and in vivo [127]. Repressive H3K27me3 and DNA methylation marks were recently reported in eNOS promoters of early EPCs, which were reversed in hypoxic conditions to increase eNOS expression, consequently increasing endothelial recruitment and differentiation [90].…”