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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4118. 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 Raines, E. W. Search for Related Content PubMed Articles by Raines, E. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Dentelli et al, page 4264 Inflamed endothelium: an EPC adhesion kit Elaine W. Raines UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE Dentelli and colleagues implicate signaling by the hematopoietic growth factor receptor c-Kit as a new mechanism for adhesion of endothelial progenitor cells (EPCs) to sites of vascular injury. While there is consensus that recruitment of bone marrow–derived endothelial progenitor cells (EPCs) to inflamed endothelium can promote repair and neovascularization, the mechanism of EPC homing to ischemic or injured sites is less well defined.1 Dissection of the mechanisms responsible for EPC adhesion and homing will allow development of strategies to improve retention and survival of EPCs, and will be critical for realization of the therapeutic potential of EPCs for rescue of ischemia and repair of blood vessels.1 In this issue of Blood, Dentelli and colleagues demonstrate that EPC adhesion to endothelial cells in vitro requires cytokine activation, and is associated with up-regulation of the membrane-bound (mb) form of the ligand (L) for the hematopoietic growth factor receptor c-Kit, mbKitL, or stem-cell factor. Specifically the authors establish that blockade or knockdown of either endothelial mbKitL or c-Kit on EPCs inhibits EPC adhesion by 70%, and the extent of this inhibition is greater than that observed with antagonists to other adhesion molecules implicated in EPC homing—ICAM 1, E-selectin, or VCAM 1. Surprisingly, EPC adhesion requires c-Kit tyrosine kinase activity and signaling. The authors further demonstrate c-Kit enhancement of EPC accumulation in vivo by implantation of endothelial cells engineered to express mbKitL in a severe combined immunodeficient (SCID) mouse model that also requires c-Kit kinase activity, and show mbKitL in endothelial cells from inflamed lesions of atherosclerosis. Taken together, the results of the study by Dentelli et al implicate EPCs' c-Kit signaling in their adhesion to inflamed vessels, including those in atherosclerosis. While integrins have been shown to contribute to EPC adhesion and homing, c-Kit involvement is unique, as this receptor is best known for its signaling in hematopoietic cells and subsequent stimulation of proliferation, differentiation, and functional activation.2 How might c-Kit signaling be involved in enhanced EPC adhesion? One possibility is that c-Kit activation by soluble KitL has been shown to modulate 4ß1 and 5ß1 integrin avidity.3 Is endothelial mbKitL modulating EPC ß1 integrin avidity or possibly other integrin signaling? Recently, 2 studies have shown integrin activation can enhance EPC adhesion and recruitment. ß2 integrin activation on EPCs increases their incorporation into ischemic tissues,4 and enhanced EPC adhesion to endothelial cells following EPC stimulation with a nuclear protein released during tissue injury is mediated by increased affinity of both ß1 and ß2 integrins on EPCs.5 Thus, it is possible that c-Kit signaling cross-talk with multiple integrins may contribute to its regulation of EPC adhesion. Consistent with this possibility, the Dentelli et al study shows that c-Kit blockade inhibits EPC adhesion more than antibodies to either of the ß1 or ß2 integrin ligands, VCAM 1 or ICAM 1, respectively. The dependence of EPC accumulation in vivo on c-Kit signaling may also reflect broader effects of c-Kit activation on EPC migration, invasion, differentiation, and/or survival.2 While a multistep process is proposed for homing of EPCs to ischemic and injured tissues,1 evaluation of the contribution of different mediators to each step will be aided by use of uniform and characterized EPC populations. The work of Dentelli and colleagues suggests that evaluation of the contribution of c-Kit signaling is warranted at possibly multiple steps. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Urbich C and Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004; 95:343–353.[Abstract/Free Full Text] Ashman LK. The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 1999; 31:1037–1051.[CrossRef][Medline] [Order article via Infotrieve] Kovach NL, Lin N, Yednock T, Harlan JM, Broudy VC. Stem cell factor modulates avidity of alpha 4 beta 1 and alpha 5 beta 1 integrins expressed on hematopoietic cell lines. Blood 1995; 85:159–167.[Abstract/Free Full Text] Chavakis E, Aicher A, Heeschen C, et al. Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 2005; 201:63–72.[Abstract/Free Full Text] Chavakis E, Hain A, Vinci M, et al. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res 2007; 100:204–212.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium Patrizia Dentelli, Arturo Rosso, Antonina Balsamo, Sofia Colmenares Benedetto, Annarita Zeoli, Marco Pegoraro, Giovanni Camussi, Luigi Pegoraro, and Maria Felice Brizzi Blood 2007 109: 4264-4271. [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 Raines, E. W. Search for Related Content PubMed Articles by Raines, E. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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