title: 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 1α (HP1α) is known to be involved in the epigenetic regulation of gene silencing. However, recent reports demonstrate that HP1α can also activate gene expression during cell differentiation. In this study, microarray analysis revealed that HP1α 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 HP1α in the differentiation of EPCs to OECs, its expression was knocked-down or over-expressed in differentiating EPCs. Overexpression of HP1α promoted the differentiation and angiogenic activity of EPCs in vitro and in vivo, whereas knockdown of HP1α 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 HP1α-overexpressing EPCs. Also, increased HP1α 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 HP1α plays an important role in the differentiation and angiogenic function of EPCs by regulating endothelial gene expression. Stem Cells 2015;33:1512-1522.
authors.affiliation: Corneal Dystrophy Research Institute; Department of Ophthalmology, Yonsei University College of Medicine, Seoul, 120-752, Korea; Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Maeng
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kwon
authors.forename: Eung Kweon
authors.initials: EK
authors.lastname: Kim
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development; D002454:Cell Differentiation; D002465:Cell Movement; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D014945:Wound Healing
chemical_list: C000715594:CBX5 protein, human; C000715595:CBX5 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D000090266:Chromobox Protein Homolog 5
keywords: Differentiation; Epigenetics; HP1α; Neovascularization