title: Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells.
abstract: CXCR4 expression is important for cell migration and recruitment, suggesting that the expression levels of CXCR4 may be correlated with functional activity of implanted cells for therapeutic neovascularization. Here, we examined differences between umbilical cord blood (CB) donors in the CXCR4 levels of endothelial colony forming cells (ECFCs), which are a subtype of endothelial progenitor cells (EPCs). We investigated the relationships between CXCR4 expression level and SDF-1alpha-induced vascular properties in vitro, and their in vivo contributions to neovascularization. We found that ECFCs isolated from different donors showed differences in CXCR4 expression that were linearly correlated with SDF-1alpha-induced migratory capacity. ECFCs with high CXCR4 expression showed enhanced ERK and Akt activation in response to SDF-1alpha. In addition, SDF-1alpha-induced migration and ERK1/2, Akt, and eNOS activation were reduced by AMD3100, a CXCR4-specific peptide antagonist, or by siRNA-CXCR4. Administration of high-CXCR4-expressing ECFCs resulted in a significant increase in therapeutic potential for blood flow recovery, tissue healing and capillary density compared to low-CXCR4-expressing ECFCs in hindlimb ischemia. Taken together, the functional differences among ECFCs derived from different donors depended on the level of CXCR4 expression, suggesting that CXCR4 expression levels in ECFCs could be a predictive marker for success of ECFC-based angiogenic therapy.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Bae Jun
authors.initials: BJ
authors.lastname: Oh
authors.forename: Deog Kyeom
authors.initials: DK
authors.lastname: Kim
authors.forename: Byoung Jae
authors.initials: BJ
authors.lastname: Kim
authors.forename: Kang-Sup
authors.initials: KS
authors.lastname: Yoon
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Park
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001596:Benzylamines; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D000080027:Cyclams; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019520:Living Donors; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017202:Myocardial Ischemia / Q000628:therapy*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; C527276:CXCR4 protein, human; C088327:plerixafor