title: Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle.
abstract: Trafficking of transplanted endothelial progenitor cells (EPCs) to ischemic tissue is enhanced by stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF). However, it has not been studied how these cytokines modulate the local milieu to entrap EPCs. This study was performed to elucidate a molecular pathway of trafficking EPCs through Akt and to test its application as an adjuvant modality to increase EPC homing. In a mouse hind limb ischemia model, systemically administered 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled mouse EPCs showed three stages of homing to ischemic limb: adhesion to endothelial cells (ECs), incorporation to capillary, and transendothelial migration into extravascular space. As an underlying mechanism to control adhesion of EPCs to ECs, we found that Akt was activated in ECs of ischemic muscle by ischemia-induced VEGF and SDF-1. In vitro and in vivo experiments using adenoviral vector for constitutively active or dominant-negative Akt genes showed that activated Akt enhanced intercellular adhesion molecule 1 (ICAM-1) expression on ECs. Akt activation in ECs also enhanced EPC incorporation to ECs and transendothelial migration in vitro experiments. Activated Akt was sufficient for induction of EPC homing even in normal hind limb, where VEGF or SDF-1 was not increased. Finally, local Akt gene transfer to ischemic limb significantly enhanced homing of systemically administered EPCs, new vessel formation, blood flow recovery, and tissue healing. Akt plays a key role in EPC homing to ischemic limb by controlling ICAM-1 and transendothelial migration. Modulation of Akt in the target tissue may be an adjunctive measure to enhance homing of systemically administered stem cells, suggesting a possibility of cell-and-gene hybrid therapy. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul 110-744, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Choon-Soo
authors.initials: CS
authors.lastname: Lee
authors.forename: Tae-Youn
authors.initials: TY
authors.lastname: Kim
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Oh
authors.forename: Kyung-Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Chae
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D006614:Hindlimb / Q000201:enzymology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000139:chemically induced / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000201:enzymology* / Q000473:pathology*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt