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First published online April 5, 2007
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2006-0385v1
25/7/1769    most recent
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Submitted on June 24, 2006
Accepted on March 26, 2007

Tissue-Specific Stem Cells

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

Jin Hur 1, Chang-Hwan Yoon 1, Choon-Soo Lee 1, Tae-Youn Kim 1, Il-Young Oh 1, Kyung-Woo Park 2, Ji-Hyun Kim 1, Hyun-Sook Lee 1, Hyun-Jae Kang 2, In-Ho Chae 2, Byung-Hee Oh 2, Young-Bae Park 2, Hyo-Soo Kim 2*

1 National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Korea
2 National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.


  Abstract

Objective: Trafficking of transplanted endothelial progenitor cells (EPCs) to ischemic tissue is enhanced by SDF-1 and 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.

Methods and results: In a mouse hindlimb ischemia model, systemically-administered DiI-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 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 hindlimb, 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.

Conclusions: 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.

Key Words. angiogenesis, endothelial progenitor cells, ischemia, cell signaling, cell adhesion molecules, gene therapy




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