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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2640-2646. Prepublished online as a Blood First Edition Paper on November 21, 2007; DOI 10.1182/blood-2007-04-086231. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-04-086231v1 111/5/2640    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Carmona, G. Articles by Dimmeler, S. PubMed PubMed Citation Articles by Carmona, G. Articles by Dimmeler, S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Activation of Epac stimulates integrin-dependent homing of progenitor cells Guillaume Carmona1, Emmanouil Chavakis1, Ulrike Koehl2, Andreas M. Zeiher1, and Stefanie Dimmeler1 1 Molecular Cardiology, Department of Internal Medicine III, and 2 Pediatric Hematology and Oncology, Department of Pediatrics III, J. W. Goethe University Frankfurt, Frankfurt, Germany Cell therapy is a novel promising option for treatment of ischemic diseases. Administered endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. However, the number of cells that home to ischemic tissues is restricted. The GTPase Rap1 plays an important role in the regulation of adhesion and chemotaxis. We investigated whether pharmacologic activation of Epac1, a nucleotide exchange protein for Rap1, which is directly activated by cAMP, can improve the adhesive and migratory capacity of distinct progenitor cell populations. Stimulation of Epac by a cAMP-analog increased Rap1 activity and stimulated the adhesion of human EPCs, CD34+ hematopoietic progenitor cells, and mesenchymal stem cells (MSCs). Specifically, short-term stimulation with a specific Epac activator increased the β2-integrin–dependent adhesion of EPCs to endothelial cell monolayers, and of EPC and CD34+ cells to ICAM-1. Furthermore, the Epac activator enhanced the β1-integrin–dependent adhesion of EPCs and MSCs to the matrix protein fibronectin. In addition, Epac1 activation induced the β1- and β2-integrin–dependent migration of EPCs on fibronectin and fibrinogen. Interestingly, activation of Epac rapidly increased lateral mobility of β1- and β2-integrins, thereby inducing integrin polarization, and stimulated β1-integrin affinity, whereas the β2-integrin affinity was not increased. Furthermore, prestimulation of EPCs with the Epac activator increased homing to ischemic muscles and neovascularization-promoting capacity of intravenously injected EPCs in the model of hind limb ischemia. These data demonstrate that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhances their in vivo therapeutic potential. These results may provide a platform for the development of novel therapeutic approaches to improve progenitor cell homing. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Epac1 activation and progenitor-cell homing Domenico Ribatti Blood 2008 111: 2501. [Full Text] [PDF] This article has been cited by other articles: S. Dimmeler and A. Leri Aging and Disease as Modifiers of Efficacy of Cell Therapy Circ. Res., June 6, 2008; 102(11): 1319 - 1330. [Abstract] [Full Text] [PDF]

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