Differences in donor CXCR4 expression levels are correlated with functional capacity and therapeutic outcome of angiogenic treatment with endothelial colony forming cells.
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.
Oh
Bae Jun
BJ
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Kim
Deog Kyeom
DK
Kim
Byoung Jae
BJ
Yoon
Kang-Sup
KS
Park
Sang Gyu
SG
Park
Kyong Soo
KS
Lee
Myung-Shik
MS
Kim
Kwang-Won
KW
Kim
Jae Hyeon
JH
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
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