Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle.
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.
Hur
Jin
J
National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul 110-744, Korea.
Yoon
Chang-Hwan
CH
Lee
Choon-Soo
CS
Kim
Tae-Youn
TY
Oh
Il-Young
IY
Park
Kyung-Woo
KW
Kim
Ji-Hyun
JH
Lee
Hyun-Sook
HS
Kang
Hyun-Jae
HJ
Chae
In-Ho
IH
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
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
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