title: 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.
authors.affiliation: 1 Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Tran Cam
authors.initials: TC
authors.lastname: Tu
authors.affiliation: 1 Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Masumi
authors.initials: M
authors.lastname: Nagano
authors.affiliation: 1 Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: 2 Department of Obstetrics and Gynecology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hamada
authors.affiliation: 3 Laboratory of Molecular Pathophysiology, Faculty of Pharmacy, Takasaki University of Health and Welfare , Takasaki, Japan .
authors.forename: Kinuko
authors.initials: K
authors.lastname: Ohneda
authors.affiliation: 1 Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kimura
authors.affiliation: 1 Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba, Japan .
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohneda
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D014945:Wound Healing; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000444:Aldehyde Dehydrogenase; D051792:Basic Helix-Loop-Helix Proteins; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D000099162:Endothelial PAS Domain-Containing Protein 1