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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2501. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ribatti, D. Search for Related Content PubMed Articles by Ribatti, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Carmona et al, page 2640 Epac1 activation and progenitor-cell homing Domenico Ribatti UNIVERSITY OF BARI MEDICAL SCHOOL The article by Carmona and colleagues in this issue of Blood demonstrates that activation of Epac1 increases integrin activity and integrin-dependent homing functions of progenitor cells and enhances their in vivo therapeutic potential. Endothelial progenitor cells (EPCs) were initially described by Asahara and coworkers in 1997,1 and the past few years have seen a rapid expansion of our knowledge of EPC biology. Prior to the discovery of this cell type, new-vessel formation was believed to result from the proliferation of existing endothelial cells. These findings have overturned the previous dogma that vasculogenesis can occur only during embryogenesis. Little is known about the mechanisms of homing and differentiation of EPCs. Homing is a complex process, involving the arrest of circulating cells within tumor microvessels, extravasation into the interstitium, and incorporation into new vessels, and is dependent on an interplay between chemokines, chemokine receptors, intracellular signaling, adhesion molecules (selectins and integrins), and proteases. Existing data support the involvement of integrins in the homing of EPCs and progenitor cells to sites of active neovascularization. Chavakis et al have demonstrated that human adult peripheral-blood–derived EPCs, murine adult bone marrow–derived EPCs, and bone marrow–derived hematopoietic progenitor/stem cells express β2 integrin.2 In an experimental study published in this issue of Blood, Carmona and colleagues investigated whether pharmacological activation of Epac1, a nucleotide exchange protein for Rap1 previously implicated in leukocyte adhesion and chemotaxis, can improve the adhesive and migratory capacity of distinct progenitor-cell populations. The authors demonstrated that stimulation of Epac1 by a cAMP analog increased Rap1 activity and stimulated the adhesion of ex vivo–expanded human EPCs, CD34+ hematopoietic progenitor cells, and mesenchymal stem cells. Furthermore, Epac1 activation induced the β1- and β2-integrin–dependent migration of EPCs on fibronectin and fibrinogen, respectively. Finally, prestimulation of EPCs with the Epac1 activator increased homing to ischemic muscles and the neovascularization-promoting capacity of in-travenously injected EPCs in the murine model of hind-limb ischemia. Overall, these data provide insights into the regulation of integrin activity in progenitor cells, and unravel a new possibility: to activate integrin-dependent homing in progenitor cells by stimulation of Epac1. The molecular and cellular mechanisms underlying EPC recruitment and differentiation are not completely understood, and remain as one of the central issues in stem-cell biology. Gaining knowledge of the molecular mechanisms that allow homing of different progenitor-cell subpopulations to sites of neovascularization is important for the development of new, specific therapeutic strategies concerning the efficacy of cell-based therapies in patients with is-chemic diseases, the ability to vascularize various engineered tissues, and the inhibition of EPC-mediated tumor neovascularization. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275:964–967.[Abstract/Free Full Text] Chavakis E, Aicher A, Heeschen C, et al. Role of beta 2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 2005; 201:63–72.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Activation of Epac stimulates integrin-dependent homing of progenitor cells Guillaume Carmona, Emmanouil Chavakis, Ulrike Koehl, Andreas M. Zeiher, and Stefanie Dimmeler Blood 2008 111: 2640-2646. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ribatti, D. Search for Related Content PubMed Articles by Ribatti, D. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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