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Close Encounters of the Third Kind

2011; Lippincott Williams & Wilkins; Volume: 31; Issue: 2 Linguagem: Inglês

10.1161/atvbaha.110.219097

1524-4636

Gaia Spinetti, Orazio Fortunato, N Kraenkel, Paolo Madeddu,

Gender, Feminism, and Media

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 31, No. 2Close Encounters of the Third Kind Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBClose Encounters of the Third KindProgenitor Cells Land on the Platelet-Enriched Vascular Surface Gaia Spinetti, Orazio Fortunato, Nicolle Kraenkel and Paolo Madeddu Gaia SpinettiGaia Spinetti From the Diabetes Research Unit, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy (G.S., O.F.); Institute of Physiology-Cardiovascular Research, University of Zurich, Zurich, Switzerland (N.K.); Institution Chair of Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (P.M.). , Orazio FortunatoOrazio Fortunato From the Diabetes Research Unit, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy (G.S., O.F.); Institute of Physiology-Cardiovascular Research, University of Zurich, Zurich, Switzerland (N.K.); Institution Chair of Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (P.M.). , Nicolle KraenkelNicolle Kraenkel From the Diabetes Research Unit, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy (G.S., O.F.); Institute of Physiology-Cardiovascular Research, University of Zurich, Zurich, Switzerland (N.K.); Institution Chair of Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (P.M.). and Paolo MadedduPaolo Madeddu From the Diabetes Research Unit, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy (G.S., O.F.); Institute of Physiology-Cardiovascular Research, University of Zurich, Zurich, Switzerland (N.K.); Institution Chair of Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (P.M.). Originally published1 Feb 2011https://doi.org/10.1161/ATVBAHA.110.219097Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:243–244Following vascular injury, endothelial cells become activated in the attempt to repave the damaged luminal surface. In addition, a physical interaction is established not only among the denuded subendothelial matrix, activated platelets, and circulating inflammatory cells but also with the progenitor cells (PCs).1 Endothelial survival, proliferation, and migration, necessary for re-coverage of exposed lamina, are aided by CD34+ PCs that express the vascular endothelial growth factor (VEGF) receptor-2/kinase-insert domain receptor (KDR). However, whether these cells enter the peripheral circulation as a predefined population or acquire their final antigenic phenotype on homing to the peripheral vasculature remains a matter of debate.See accompanying article on page 408In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, de Boer et al propose that human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets.2 By using an ex vivo flow model, the authors show that activated platelets favor the homing of CD34+ cells to sites of vascular injury and that, on cell immobilization, KDR is rapidly translocated from an endosomal compartment to the cell surface. Presumably, PCs shed afterward to "carry the message" into the circulation. It is noteworthy that de Boer et al also report an increased coexpression of KDR on CD34+ cells in type-2 diabetes, which was reduced by aspirin treatment. The authors conclude that their data might have implications for the identification of patients with subclinical vascular injury, on the basis of the hypothesis that activated/injured endothelium provides more opportunity for platelet-CD34+ PC interaction.The analysis of the PC antigenic profile could represent an attractive means by which to verify the status of vascular health and monitor the progression of vascular disease. In fact, different PC readouts from a patient's blood sample might hint at distinct adaptive responses to specific environmental cues from the peripheral vasculature. The appropriate interpretation of such complex phenomena is hindered in part by current limitations in the standardization of flow cytometry analysis, leading to large variations in the absolute and relative expression of surface antigens. In their study, de Boer et al apply state-of-the-art technology, including the use of counting beads (for the acquisition of absolute numbers of cells per volume of blood) and a multiparametric gating strategy based on the International Society of Hematotherapy and Graft Engineering protocol. Using a similar strategy, Schmidt-Lucke et al have recently shown that CD45dimCD34+KDR+ PCs correlate inversely with the grade of coronary artery disease and are increased by statin treatment, thereby possibly serving as a biomarker of endothelial status.3One puzzling aspect of the study by de Boer et al is represented by the remarkably low levels of KDR expression on the surface of CD34+ cells from healthy controls. Although KDR was found to be variably expressed, previous reports showed values 10-fold higher than the figure reported in de Boer's study. Furthermore, a large body of evidence indicates a reduction rather than an increase in KDR expression in diabetes.3–5 A recent metaanalysis of 4 longitudinal studies including 1,057 patients showed that low abundance of CD34+KDR+ PCs is associated with a higher risk of major adverse cardiovascular events.6 On the other hand, we found that in type-1 diabetic patients free from cardiovascular complications except mild background retinopathy, the number of circulating CD34+KDR+ PCs is similar to that of age-matched controls; nevertheless, functional deficits were detected in the fraction of diabetic cells that migrate toward a chemoattractant.7 Thus, functional analysis might provide useful information at an early stage, before the antigenic profile becomes altered. One possible explanation for the apparent discrepancy in KDR+ counts is that pharmacological treatment can confound the final readout. However, apart from statin and aspirin, common cardiovascular drugs reportedly do not have an influence on CD34+KDR+ numbers.8 Another aspect, the resistance to VEGF signals in diabetes, was recently studied by Tchaikovski et al in monocytes.9 Because of the preactivation of intracellular signaling pathways in cells derived from diabetic donors, VEGF was unable to induce further specific cellular activation. Directly equating cell function with KDR expression on CD34+ PCs might therefore be misleading.The proposal that cellular interaction induces KDR surface expression on CD34+ cells raises further questions (Figure). If CD34+KDR+ cells are more adhesive than CD34+KDR− cells, why are the former augmented in the circulation of diabetic patients rather than remaining adherent to the vessel wall? In a broader context, can detached PCs carry messages from tissues and the vessel wall back to the circulation and finally the bone marrow (BM)? Are adhering/circulating cells in dynamic equilibrium with cells continuously released from the BM? To enter the circulation, BM cells have to pass the endothelial sinusoid barrier. Is this an additional site for KDR induction on transmigrating cells? The authors show that the abundance of KDR+ on CD34+ cells does not increase after active mobilization with granulocyte colony-stimulating factor, which is supportive of KDR being a peripheral addendum. However, granulocyte colony-stimulating factor–induced mobilization could be rapid enough to minimize KDR translocation on CD34+ cell surface during transendothelial migration. A recent study from our group showed an increased adhesion of BM-derived PCs to diabetic BM endothelial cells under static conditions and after introduction of shear flow.10 This enhanced adhesive contact may facilitate the acquisition of endothelial antigens like KDR by transmigrating CD34+ cells. It would be relevant to investigate whether aspirin treatment results in a more rapid transmigration of KDR− PCs into the circulation.Download figureDownload PowerPointFigure. As presented by de Boer et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, platelets on a vascular lesion may stimulate KDR externalization in CD34+ cells (black arrows). However, several questions remain open (grey arrows and numbers). (1) Can BM cells acquire KDR while passing the vascular sinusoid barrier to reach the circulation? (2) Can endothelial-associated transcription factors and microRNAs, among other factors, deliver messages that induce KDR expression? (3) Can platelet-derived KDR be transferred to CD34+ cells? (4) If CD34+/KDR+ cells firmly adhere to the activation site, why they are found augmented in diabetes? (5) Can CD34+/KDR+ cells carry messages back to the BM? (6) Are cells in dynamic equilibrium between circulation and BM? (7) Does the analysis of the circulating cells truly reflect what is happening at the vascular level?Furthermore, alternative mechanisms might also explain the presence of KDR on adhering CD34+ PC surface. It was proposed that platelet-derived microparticles start to cover PCs immediately after their entry into the bloodstream from the BM and thereby enhance the adhesive capacities of PCs.11 Putative endothelial markers, such as CD31 and von Willebrand factor, are also abundant on platelets. In addition, platelets contain cryptic VEGF receptors, including KDR, which become exposed on the platelet membrane following stimulation by VEGF. It is therefore possible that, as shown for other endothelial antigens, KDR is exchanged from platelets to adherent PCs.12 Finally, transcription factors, small molecules, and microRNAs could be delivered during transient or firm interactions with the endothelium, thereby inducing specific responses, including expression of surface antigens, in target cells.13 The capacity of recipient cells to selectively elaborate the donated material suggests that these are close encounters that leave a sign.Sources of FundingThis work was supported by a strategic grant from the Medical Research Council, "Function-Based Enrichment of Proangiogenic Cells for Cardiac Repair" (to P.M.). Dr Kraenkel is supported by a fellowship of the Swiss National Science Foundation.DisclosuresNone.FootnotesCorrespondence to Paolo Madeddu, Experimental Cardiovascular Medicine, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, United Kingdom. E-mail [email protected]comReferences1. Weber C, Schober A, Zernecke A. Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol. 2004; 24:1997–2008.LinkGoogle Scholar2. de Boer H, Hovens M, van Oeveren A, Snoep J, de Koning E, Tamsma J, Huisman M, Rabelink T, van Zonneveld AJ. Human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets. Arterioscler Thromb Vasc Biol. 2011; 31:408–415.LinkGoogle Scholar3. Schmidt-Lucke C, Fichtlscherer S, Aicher A, Tschope C, Schultheiss HP, Zeiher AM, Dimmeler S. Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol. PLoS One. 2010; 5:e13790.CrossrefMedlineGoogle Scholar4. Jialal I, Devaraj S, Singh U, Huet BA. Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk. Atherosclerosis. 2010; 211:297–302.CrossrefMedlineGoogle Scholar5. Grundmann F, Scheid C, Braun D, Zobel C, Reuter H, Schwinger RH, Muller-Ehmsen J. Differential increase of CD34, KDR/CD34, CD133/CD34 and CD117/CD34 positive cells in peripheral blood of patients with acute myocardial infarction. Clin Res Cardiol. 2007; 96:621–627.CrossrefMedlineGoogle Scholar6. Fadini GP, Maruyama S, Ozaki T, Taguchi A, Meigs J, Dimmeler S, Zeiher AM, de Kreutzenberg S, Avogaro A, Nickenig G, Schmidt-Lucke C, Werner N. Circulating progenitor cell count for cardiovascular risk stratification: a pooled analysis. PLoS One. 2010; 5:e11488.CrossrefMedlineGoogle Scholar7. Krankel N, Armstrong SP, McArdle CA, Dayan C, Madeddu P. Distinct kinin-induced functions are altered in circulating cells of young type 1 diabetic patients. PLoS One. 2010; 5:e11146.CrossrefMedlineGoogle Scholar8. Fadini GP, Boscaro E, de Kreutzenberg S, Agostini C, Seeger F, Dimmeler S, Zeiher A, Tiengo A, Avogaro A. Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes. Diabetes Care. 2010; 33:1097–1102.CrossrefMedlineGoogle Scholar9. Tchaikovski V, Olieslagers S, Bohmer FD, Waltenberger J. Diabetes mellitus activates signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes. Circulation. 2009; 120:150–159.LinkGoogle Scholar10. Oikawa A, Siragusa M, Quaini F, Mangialardi G, Katare RG, Caporali A, van Buul JD, van Alphen FP, Graiani G, Spinetti G, Kraenkel N, Prezioso L, Emanueli C, Madeddu P. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol. 2010; 30:498–508.LinkGoogle Scholar11. Janowska-Wieczorek A, Majka M, Kijowski J, Baj-Krzyworzeka M, Reca R, Turner AR, Ratajczak J, Emerson SG, Kowalska MA, Ratajczak MZ. Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment. Blood. 2001; 98:3143–3149.CrossrefMedlineGoogle Scholar12. Prokopi M, Pula G, Mayr U, Devue C, Gallagher J, Xiao Q, Boulanger CM, Westwood N, Urbich C, Willeit J, Steiner M, Breuss J, Xu Q, Kiechl S, Mayr M. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood. 2009; 114:723–732.CrossrefMedlineGoogle Scholar13. Mause SF, Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res. 2010; 107:1047–1057.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 2011Vol 31, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.110.219097PMID: 21248281 Originally publishedFebruary 1, 2011 Keywordsatherosclerosisplateletsdiabetes mellitusendothelial progenitor cellsaspirinPDF download Advertisement SubjectsDiabetes, Type 2Endothelium/Vascular Type/Nitric OxidePlatelets