A Chemokine Receptor, CXCR4, Which Is Regulated by Hypoxia-Inducible Factor 2α, Is Crucial for Functional Endothelial Progenitor Cells Migration to Ischemic Tissue and Wound Repair

Abstract

Endothelial progenitor cells (EPCs) have the ability to form new blood vessels and protect ischemic tissues from damage. We previously reported that EPCs with low activity of aldehyde dehydrogenase (Alde-Low EPCs) possess the greater ability to treat ischemic tissues compared with Alde-High EPCs. The expression level of the hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, was found to be greater in Alde-Low EPCs than in Alde-High EPCs. However, the precise role of the HIF factors in the regulation of EPC activity remains obscure. In this study, we demonstrate a critical role of HIF-2α and its target gene CXCR4 for controlling the migratory activity of EPC to ischemic tissue. We found that coculture of Alde-High EPCs with microvesicles derived from Alde-Low EPCs improved their ability to repair an ischemic skin flap, and the expression of CXCR4 and its ligand SDF1 was significantly increased following the coculture. In Alde-Low EPCs, the expression of CXCR4 was suppressed by short hairpin RNA (shRNA)-mediated HIF-2α, but not HIF-1α downregulation. Chromatin immunoprecipitation assays showed that HIF-2α, but not HIF-1α, binds to the promoter region of CXCR4 gene. The CXCR4 shRNA treatment in Alde-Low EPCs almost completely abrogated their migratory activity to ischemic tissues, whereas the reduction of vascular endothelial growth factor (VEGF) showed much less effect. The CXCR4 overexpression in Alde-High EPCs resulted in a partial, but significant improvement in their repairing ability in an ischemic skin flap. Collectively, these findings indicate that the CXCR4/SDF-1 axis, which is specifically regulated by HIF-2α, plays a crucial role in the regulation of EPC migration to ischemic tissues.

MiR-206 Suppresses the Progression of Coronary Artery Disease by Modulating Vascular Endothelial Growth Factor (VEGF) Expression

“…Endothelium damage starts the mobilization of circulating EPCs derived from the bone marrow; these EPCs target the damage site, differentiate into mature endothelial cells, integrate into the endothelium, and replace apoptotic or injured cells [22,23]. Therefore, circulating EPCs that contribute to endothelial functions play an indispensable role in endogenous refurbishment and CVD pathogenesis.…”

Erythropoietin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in an Aneurysm Neck After Coil Embolization by Modulating Vascular Endothelial Growth Factor

“…The exact and detailed mechanism through which EPO affects endothelialization remains unclear. Other important factors in addition to VEGF may be involved, such as hypoxia inducible factor 1 and stromal-derived factor 1, which are also known to mobilize EPCs under conditions of vascular disease and injury [39][40][41]. Further studies are required to explore the mechanism responsible for the EPO-based endothelialization of aneurysm necks.…”

Co‐transplantation of Wharton's jelly mesenchymal stem cell‐derived osteoblasts with differentiated endothelial cells does not stimulate blood vessel and osteoid formation in nude mice models

“…The absence of VEGF secretion observed in vitro with WJMSC‐OBs might again explain the observed results. The interaction between SDF1 and its receptor CXCR4 is also believed to be an important contributor to the regulation of EPC migration in ischemic tissue (Tu et al, ). In BM, OBs express SDF‐1, which acts as a chemoattractant for hematopoietic stem cells (Ponomaryov et al, ).…”

“…Furthermore, a growing body of evidence suggests that MSCs have a predominant paracrine role in promoting tissue regeneration (Gnecchi, Danieli, Malpasso, & Ciuffreda, ). The stromal cell‐derived factor 1 (SDF‐1)/C‐X‐C chemokine receptor type 4 (CXCR4) pathway and vascular endothelial growth factor (VEGF) seem to be critical for the migration of cells to injured sites and for subsequent bone and blood vessel formation (Kitaori et al, ; Tu et al, ; Zhou et al, ).…”