gms | German Medical Science

24. Jahrestagung der Deutschen Gesellschaft für Arterioskleroseforschung

Deutsche Gesellschaft für Arterioskleroseforschung

18.03. - 20.03.2010, Blaubeuren

Expression of stromal cell-derived factor-1 on the surface of circulating platelets: from molecular interactions to clinical significance

Meeting Contribution

  • corresponding author Konstantinos Stellos - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany
  • Kateryna Sopova - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany
  • Stephan Gnerlich - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany
  • Victoria Panagiota - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany
  • Angela Paul - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany
  • Meinrad Gawaz - Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany

Deutsche Gesellschaft für Arterioskleroseforschung e.V.. 24. Jahrestagung der Deutschen Gesellschaft für Arterioskleroseforschung. Blaubeuren, 18.-20.03.2010. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc10dgaf04

doi: 10.3205/10dgaf04, urn:nbn:de:0183-10dgaf044

Veröffentlicht: 23. März 2011

© 2011 Stellos et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


The chemokine stromal cell-derived factor-1 (SDF-1) regulates leukocyte and progenitor cell trafficking from bone marrow to peripheral circulation and subsequently to tissue lesions. Platelets express substantial amounts of SDF-1 upon activation mediating the recruitment of progenitor cells on inflammatory endothelium and their differentiation into endothelial cells or macrophages. Absence of platelets results in decreased SDF-1 blood levels and into a defected tissue healing process, indicating that platelet-derived SDF-1 is crucially involved in progenitor cell-mediated tissue repair in vivo. Patients in need of vascular and/or myocardial repair, such as patients with reduced left ventricular function or patients with acute myocardial infarction, present with increased expression levels of platelet-derived SDF-1. Recently, a novel receptor for SDF-1 has been described, the so called CXCR7. Further studies are needed to elucidate the pathways of platelet-derived SDF-1 function in vascular homeostasis. The aim of the present review is to summarize the recently described role of platelet-derived SDF-1 in interaction with blood cells and especially progenitor cells and its potential clinical significance in patients with ischemic heart disease.

Platelet-derived SDF-1 interacts with CXCR4-positive cells

The stromal cell-derived factor-1 (SDF-1; CXCL12) is the most potent chemokine of stem and progenitor cells, as well as of monocytes, lymphocytes and platelets [1], [2], [3]. SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in the direct proportion to reduced oxygen tension [4]. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue [4]. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury [4]. Interestingly, forced expression of SDF-1 in the heart by adenoviral gene delivery 48 hours after myocardial infarction doubled bone marrow-derived cell recruitment over myocardial infarction alone [5]. It has been recently reported by our research group and another group that high amounts of SDF-1 is stored in platelets and is expressed on the surface of platelets and subsequently secreted after platelet activation or adhesion on sites of vascular injury [6], [7], [8], stimulating thereby the recruitment of murine and human progenitor cells on vascular lesions and the subsequent differentiation to endothelial cells enhancing vascular regeneration and angiogenesis in vivo. Interestingly, SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in thrombocytopenic mice, indicating that platelet-derived SDF-1 is the main key player of the SDF-1 mediated tissue regeneration in vivo. Moreover, we could also show that adherent platelets on human arterial endothelial cells mediated the recruitment of human CD34+ cells under flow conditions in a larger extent than TNF-alpha/INF-gamma-induced inflammatory endothelium in vitro [8]. Since SDF-1 activates beta-2 integrins [9], we further investigated the role of platelet-derived SDF-1 and JAM-A (junctional adhesion molecule-A) in adhesion of progenitor cells over immobilized platelets reporting that SDF-1 mediated recruitment of CD34+ cells involved the JAM-A-JAM-A and JAM-A-LFA-1 interactions [10].

Platelet mediated recruitment of progenitor cells does not only result in vasculogenesis and tissue regeneration, but also could enhance atheroprogression since platelets recruit also smooth muscle progenitor cells or can induce a differentiation of CD34+ progenitor cells towards a monocyte/foam cell phenotype [11]. A crucial role of platelets and SDF-1/CXCR4 axis has been established in the recruitment of bone marrow-derived smooth muscle progenitor cells from the circulation in response to arterial injury and apoptosis giving rise to neointimal smooth muscle cells and mediating neointimal hyperplasia. We have recently documented that SDF-1 is an essential modulator of platelet aggregates- induced differentiation of progenitor cells to macrophages/foam cells in vitro. This differentiation could be attributed to platelet phagocytosis by progenitor cells. Since platelet adhesion to the endothelium is enhanced at site of atherogenesis and in the microcirculation of ischemic tissue during reperfusion, our findings indicate that platelet thrombi could influence the fate of progenitor cells on vascular wall causing their differentiation not only into endothelial cells, but also into macrophages and foam cells instead of endothelial cells (Figure 1 [Fig. 1]).

Platelet-derived SDF-1 expression: clinical significance

The clinical significance of platelet-derived SDF-1 in a human atherosclerotic disease has only recently been reported. Increased platelet activation occurs in patients with acute myocardial infarction, measured by P-selectin expression [12]. We therefore hypothesized, that platelet-derived SDF-1 expression might be increased in patients in need of vascular and myocardial regeneration. Indeed, in a relatively large clinical study of n=904 patients with coronary artery disease undergoing coronary angiography we could show that platelet-derived SDF-1 expression was increased in patients with acute myocardial infarction or with reduced left ventricular function and correlated with platelet activation (P-selectin expression) and also with the number of circulating CD34+/CD133+ progenitor cells [13].

Platelet-derived SDF-1 expression and its novel receptor CXCR7: future perspectives

For many years, it was believed that CXCR4, a G protein-coupled signaling receptor, was the only receptor for SDF-1 [14]. As early as in September 2006, Burns JM et al. have reported that SDF-1 regulation is mediated by a second receptor, previously known as orphan RDC1 receptor, which later was renamed as CXCR7 [15]. Burns JM et al. reported that unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration, while its expression provides tumor cells with a growth and survival advantage and increased adhesion properties [15]. CXCR7 is expressed during heart embryogenesis and plays an essential role especially for the heart valve formation [16]. Cells expressing CXCR7 include human and mouse endothelial cells, human renal progenitor cells, mouse CD34+ cells and different blood cells like monocytes, T and B cells, natural killer cells, baseophils, neutrophils and immature dendritic cells [15], [17], [18], [19]. Furthermore, CXCR7 deficient mice die perinatal and postnatal [20] with severe heart defects, which is similar to mice deficient in SDF-1 or CXCR4. CXCR7 is involved in rapid SDF-1 triggered integrin activation [21]. Furthermore, the neutralization of CXCR7 inhibits the tissue regeneration and the renal function improvement in mice with acute renal failure and reduces the number of the renal multipotent progenitors [22]. CXCR4 activates G-protein coupled signaling pathways, like PI-PLC and PI3, and PKC-ζ [23]. In contrast, CXCR7 affects two signaling pathways: 1) CXCR7 heterodimerizes with CXCR4 and thus influences indirectly the SDF-1-mediated G protein-coupled signaling pathways although CXCR7 per se has no influence on this signaling pathway [24]. 2) CXCR7 activates β-arrestin, and MAP kinases [25]. To make matters more complicated, SDF-1 is cleaved by CD26/DPP-IV and MMPs [26], [27].

The mechanisms lying underneath the potential balance between injury and repair are partially known and future studies are needed to elucidate the role of platelet-derived SDF-1 interactions with CXCR4+ and CXCR7+ cells in vascular homeostasis.


Aiuti A,Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood. J Exp Med. 1997;185(1):111-20. DOI: 10.1084/jem.185.1.111 Externer Link
Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996;382:829-33. DOI: 10.1038/382829a0 Externer Link
Kraemer BF, Borst O, Gehring EM, Schoenberger T, Urban B, Ninci E, Seizer P, Schmidt C, Bigalke B, Koch M, Martinovic I, Daub K, Merz T, Schwanitz L, Stellos K, Fiesel F, Schaller M, Lang F, Gawaz M, Lindemann S. PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). J Mol Med. 2010;88(12):1277-88. DOI: 10.1007/s00109-010-0680-8 Externer Link
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine. 2004;10:858-64. DOI: 10.1038/nm1075 Externer Link
Abbott DJ, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal Cell-Derived Factor-1 Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction but Is Not Sufficient to Induce Homing in the Absence of Injury. Circulation. 2004;110:3300-5. DOI: 10.1161/01.CIR.0000147780.30124.CF Externer Link
Massberg S, Konrad I, Schürzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S, Schulz C, Kerstan S, Rudelius M, Seidl S, Sorge F, Langer H, Peluso M, Goyal P, Vestweber D, Emambokus NR, Busch DH, Frampton J, Gawaz M. Platelets secrete stromal cell-derived factor 1-alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med. 2006;203(5):1221-33. DOI: 10.1084/jem.20051772 Externer Link
Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, Hooper AT, Amano H, Avecilla ST, Heissig B, Hattori K, Zhang F, Hicklin DJ, Wu Y, Zhu Z, Dunn A, Salari H, Werb Z, Hackett NR, Crystal RG, Lyden D, Rafii S. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med. 2006;12:557-67. DOI: 10.1038/nm1400 Externer Link
Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, Bigalke B, Mueller I, Schumm M, Schaefer I, Seizer P, Kraemer BF, Siegel-Axel D, May AE, Lindemann S, Gawaz M. Platelet-Derived Stromal Cell-Derived Factor-1 Regulates Adhesion and Promotes Differentiation of Human CD34+ Cells to Endothelial Progenitor Cells. Circulation. 2008;117:206-15. DOI: 10.1161/CIRCULATIONAHA.107.714691 Externer Link
Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S, Grabovsky V, Slav MM, Nagler A, Lider O, Alon R, Zipori D, Lapidot T. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000; 95(11):3289-96.
Stellos K, Langer H, Gnerlich S, Panagiota V, Paul A, Schönberger T, Ninci E, Menzel D, Mueller I, Bigalke B, Geisler T, Bültmann A, Lindemann S, Gawaz M. Junctional Adhesion Molecule A Expressed on Human CD34+ Cells Promotes Adhesion on Vascular Wall and Differentiation Into Endothelial Progenitor Cells. Arterioscler Thromb Vasc Biol. 2010;30:1127. DOI: 10.1161/ATVBAHA.110.204370 Externer Link
Stellos K, Kopf S, Paul A, Marquardt JU, Gawaz M, Huard J, Langer HF. Platelets in regeneration. Semin Thromb Hemost. 2010;36(2):175-84. DOI: 10.1055/s-0030-1251502 Externer Link
Stellos K, Bigalke B, Stakos D, Henkelmann N, Gawaz M. Platelet-bound P-selectin expression in patients with coronary artery disease: impact on clinical presentation and myocardial necrosis, and effect of diabetes mellitus and anti-platelet medication. J Thromb Haemost. 2010;8(1):205-7. DOI: 10.1111/j.1538-7836.2009.03659.x Externer Link
Stellos K, Bigalke B, Langer H, Geisler T, Schad A, Kögel A, Pfaff F, Stakos D, Seizer P, Müller I, Htun P, Lindemann S, Gawaz M. Expression of stromal-cell-derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells. Eur Heart J. 2009;30(5):584-93. DOI: 10.1093/eurheartj/ehn566 Externer Link
Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata, K Kataoka Y, Kitamura Y, Matsushima K, Yoshida N, Nishikawa SI, Kishimoto T, Nagasawa T. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998;393:591-4. DOI: 10.1038/31261 Externer Link
Burns JM, B. Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold MET, Sunshine MJ, Littman DR;. Kuo CJ, Wie K, McMaster BE, Wright K, Howard MC, Schall TJ. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203(9):2201-2213. DOI: 10.1084/jem.20052144 Externer Link
Sierro F, Biben C, Martínez-Muñoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martínez-A C, Mackay CR, Mackay F. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci U S A. 2007;104(37):14759-64. DOI: 10.1073/pnas.0702229104 Externer Link
Balabanian K, Lagane B, Infantino S, Chow KYC, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The Chemokine SDF-1/CXCL12 Binds to and Signals through the Orphan Receptor RDC1 in T Lymphocytes. J Biol Chem. 2005;280:35760-6. DOI: 10.1074/jbc.M508234200 Externer Link
Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A. 2007;104(40):15735-40. DOI: 10.1073/pnas.0610444104 Externer Link
Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, Wilson D, Xu Q, Raz E. Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Cell. 2008;132(3):337-9. DOI: 10.1002/dvg.20387 Externer Link
Gerrits H, van Ingen Schenau DS, Bakker NEC, van Disseldorp AJM, Strik A, Hermens LS, Koenen TB, Krajnc-Franken MAN, Gossen JA. Early postnatal lethality and cardiovascular defects in CXCR7-deficient mice. Genesis. 2008;46(5):235-45. DOI: 10.1002/dvg.20387 Externer Link
Hartmann TN, Leick M, Ewers S, Diefenbacher A, Schraufstatter I, Honczarenko M, Burger M. Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. J Leukoc Biol. 2008;125(2):252-62. DOI: 10.1084/jem.20071903 Externer Link
Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M , Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homingof human renal progenitor cells. J Exp Med. 2008;205(2):479-90. DOI: 10.1084/jem.20071903 Externer Link
Petit I, Goichberg P, Spiegel A, Peled A, Brodie C, Seger R, Nagler A, Alon R, Lapidot T. Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells. J Clin Invest. 2005;115(1):168-76. DOI: 10.1073/pnas.1005636107 Externer Link
Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 2009; 11;113(24):6085-93.
Rajagopalan S, Long EO. Antagonizing inhibition gets NK cells going. PNAS. 2010;107(23):10333-4. DOI: 10.1073/pnas.1005636107 Externer Link
Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM. Synergy between CD26/DPP-IV Inhibition and G-CSF Improves Cardiac Function after Acute Myocardial Infarction. Cell Stem Cell. 2009;4(4):313-23. DOI: 10.1016/j.stem.2009.02.013 Externer Link
McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM. Matrix Metalloproteinase Activity Inactivates the CXC Chemokine Stromal Cell-derived Factor-1. J Biol Chem. 2001;276:43503-8. DOI: 10.1074/jbc.M107736200 Externer Link