HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 2006-0385v1 25/7/1769    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hur, J. Articles by Kim, H.-S. Search for Related Content PubMed PubMed Citation Articles by Hur, J. Articles by Kim, H.-S.

TISSUE-SPECIFIC STEM CELLS

Akt Is a Key Modulator of Endothelial Progenitor Cell Trafficking in Ischemic Muscle

^aNational Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Korea;
^bDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Korea

Key Words. Angiogenesis • Endothelial progenitor cells • Ischemia • Cell signaling • Cell adhesion molecules • Gene therapy

Correspondence: Hyo-Soo Kim, M.D., Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea. Telephone: 82-2-2072-2226; Fax: 82-2-766-8904; e-mail: hyosoo{at}snu.ac.kr

Received June 24, 2006; accepted for publication March 26, 2007.
First published online in STEM CELLS EXPRESS   April 5, 2007.



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.

This article has been cited by other articles:

				H. Shao, Y. Tan, D. Eton, Z. Yang, M. G. Uberti, S. Li, A. Schulick, and H. Yu Statin and Stromal Cell-Derived Factor-1 Additively Promote Angiogenesis by Enhancement of Progenitor Cells Incorporation into New Vessels Stem Cells, May 1, 2008; 26(5): 1376 - 1384. [Abstract] [Full Text] [PDF]

				I.-Y. Oh, C.-H. Yoon, J. Hur, J.-H. Kim, T.-Y. Kim, C.-S. Lee, K.-W. Park, I.-H. Chae, B.-H. Oh, Y.-B. Park, et al. Involvement of E-selectin in recruitment of endothelial progenitor cells and angiogenesis in ischemic muscle Blood, December 1, 2007; 110(12): 3891 - 3899. [Abstract] [Full Text] [PDF]