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Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle.
Stem Cells. 2007 Jul; 25(7):1769-78.SC

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+Show Affiliations

National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul 110-744, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17412896

Citation

Hur, Jin, et al. "Akt Is a Key Modulator of Endothelial Progenitor Cell Trafficking in Ischemic Muscle." Stem Cells (Dayton, Ohio), vol. 25, no. 7, 2007, pp. 1769-78.
Hur J, Yoon CH, Lee CS, et al. Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle. Stem Cells. 2007;25(7):1769-78.
Hur, J., Yoon, C. H., Lee, C. S., Kim, T. Y., Oh, I. Y., Park, K. W., Kim, J. H., Lee, H. S., Kang, H. J., Chae, I. H., Oh, B. H., Park, Y. B., & Kim, H. S. (2007). Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle. Stem Cells (Dayton, Ohio), 25(7), 1769-78.
Hur J, et al. Akt Is a Key Modulator of Endothelial Progenitor Cell Trafficking in Ischemic Muscle. Stem Cells. 2007;25(7):1769-78. PubMed PMID: 17412896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle. AU - Hur,Jin, AU - Yoon,Chang-Hwan, AU - Lee,Choon-Soo, AU - Kim,Tae-Youn, AU - Oh,Il-Young, AU - Park,Kyung-Woo, AU - Kim,Ji-Hyun, AU - Lee,Hyun-Sook, AU - Kang,Hyun-Jae, AU - Chae,In-Ho, AU - Oh,Byung-Hee, AU - Park,Young-Bae, AU - Kim,Hyo-Soo, Y1 - 2007/04/05/ PY - 2007/4/7/pubmed PY - 2007/8/2/medline PY - 2007/4/7/entrez SP - 1769 EP - 78 JF - Stem cells (Dayton, Ohio) JO - Stem Cells VL - 25 IS - 7 N2 - 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. SN - 1066-5099 UR - https://www.unboundmedicine.com/medline/citation/17412896/Akt_is_a_key_modulator_of_endothelial_progenitor_cell_trafficking_in_ischemic_muscle_ L2 - https://doi.org/10.1634/stemcells.2006-0385 DB - PRIME DP - Unbound Medicine ER -