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Differential chemokine receptor expression regulates functional specialization of endothelial progenitor cell subpopulations

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Abstract

Postnatal vasculogenesis is mediated by endothelial progenitor cells (EPCs) which consist of subpopulations with different functional capacities. Our goal was to profile chemokine receptor expression on relevant subsets of EPCs and to characterize their role for effector functions. CD34+/CD133+/VEGFR2+ EPCs were characterized by high expression of chemokine receptors CXCR4, CX3CR1, BLT1, and low level expression of CXCR2 and CCR2, while primordial CD34−/CD133+/VEGFR2+ EPCs express these chemokine receptors at comparably low levels. Migration assays revealed that SDF-1, fractalkine, and LTB4 significantly increase migration of CD34−/CD133+/VEGFR2+ EPCs, while SDF-1 was the only potent agonist of migration of CD34+/CD133+/VEGFR2+ EPCs. SDF-1, fractalkine, and LTB4 trigger significant increase adhesion of CD34+/CD133+/VEGFR2+ EPCs, while in CD34−/CD133+/VEGFR2+ EPCs SDF-1 and fractalkine are equipotent agonists and LTB4 triggers a smaller though still significant increase in adhesion. Differential expression of specific chemokine receptors is an important regulator in terms of migration and adhesion of biologically relevant EPC-subpopulations, which may have implications for cell therapeutic strategies for treatment of ischemic vascular disease.

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References

  1. Aicher A, Rentsch M, Sasaki K, Ellwart JW, Fändrich F, Siebert R, Cooke JP, Dimmeler S, Heeschen C (2007) Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res 100:581–589. doi:10.1161/01.RES.0000259562.63718.35

    Article  CAS  PubMed  Google Scholar 

  2. Asahara T, Murohara T, Sullivan A, Silver M, van der Z.R, Li T, Witzenbichler B, Schatteman G, and Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

  3. Ashida N, Arai H, Yamasaki M, Kita T (2001) Differential signaling for MCP-1-dependent integrin activation and chemotaxis. Ann N Y Acad Sci 947:387–389. doi:10.1126/science.275.5302.964

    Article  CAS  PubMed  Google Scholar 

  4. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, Grünwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM (2002) Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106:3009–3017. doi:10.1161/01.CIR.0000043246.74879.CD

    Article  PubMed  Google Scholar 

  5. Assmus B, Honold J, Schächinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM (2006) Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 355:1222–1232. doi:10.1056/NEJMoa051779

    Article  CAS  PubMed  Google Scholar 

  6. Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621. doi:10.1056/NEJMra052723

    Article  CAS  PubMed  Google Scholar 

  7. Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, Emmrich F, Kluge R, Kendziorra K, Sabri O, Schuler G, Hambrecht R (2005) Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res 97:756–762. doi:10.1161/01.RES.0000185811.71306.8b

    Article  CAS  PubMed  Google Scholar 

  8. Eriksson EE (2004) Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol 15:553–558. doi:10.1097/00041433-200410000-00009

    Article  CAS  PubMed  Google Scholar 

  9. Friedrich EB, Werner C, Walenta K, Böhm M, Scheller B (2009) Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease. Basic Res Cardiol 104:613–620. doi:10.1007/s00395-009-0022-6

    Article  CAS  PubMed  Google Scholar 

  10. Friedrich EB, Tager AM, Liu E, Pettersson A, Owman C, Munn L, Luster AD, Gerszten RE (2003) Mechanisms of leukotriene B4-triggered monocyte adhesion. Arterioscler Thromb Vasc Biol 23:1761–1767. doi:10.1161/01.ATV.0000092941.77774.3C

    Article  CAS  PubMed  Google Scholar 

  11. Friedrich EB, Clever YP, Wassmann S, Hess C, Nickenig G (2006) 17Beta-estradiol inhibits monocyte adhesion via down-regulation of Rac1 GTPase. J Mol Cell Cardiol 40:87–95. doi:10.1016/j.yjmcc.2005.10.007

    Article  CAS  PubMed  Google Scholar 

  12. Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N (2006) CD34−/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res 98:e20–e25. doi:10.1161/01.RES.0000205765.28940.93

    Article  CAS  PubMed  Google Scholar 

  13. Hristov M, Zernecke A, Bidzhekov K, Liehn EA, Shagdarsuren E, Ludwig A, Weber C (2007) Importance of CXC chemokine receptor 2 in the homing of human peripheral blood endothelial progenitor cells to sites of arterial injury. Circ Res 100:590–597. doi:10.1161/01.RES.0000259043.42571.68

    Article  CAS  PubMed  Google Scholar 

  14. Hristov M, Zernecke A, Liehn EA, Weber C (2007) Regulation of endothelial progenitor cell homing after arterial injury. Thromb Haemost 98:274–277. doi:10.1160/TH07-03-0181

    CAS  PubMed  Google Scholar 

  15. Jung C, Fischer N, Fritzenwanger M, Thude H, Ferrari M, Fabris M, Brehm BR, Barz D, Figulla HR (2009) Endothelial progenitor cells in adolescents: impact of overweight, age, smoking, sport and cytokines in younger age. Clin Res Cardiol 98:179–188. doi:10.1007/s00392-008-0739-5

    Article  CAS  PubMed  Google Scholar 

  16. Kaur S, Kumar TR, Uruno A, Sugawara A, Jayakumar K, Kartha CC (2009) Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study. Basic Res Cardiol 104:739–749. doi:10.1007/s00395-009-0039-x

    Article  PubMed  Google Scholar 

  17. Keymel S, Kalka C, Rassaf T, Yeghiazarians Y, Kelm M, Heiss C (2008) Impaired endothelial progenitor cell function predicts age-dependent carotid intimal thickening. Basic Res Cardiol 103:582–586. doi:10.1007/s00395-008-0742-z

    Article  PubMed  Google Scholar 

  18. Kleinbongard P, Weber AA (2008) Impaired interaction between platelets and endothelial progenitor cells in diabetic patients. Basic Res Cardiol 103:569–711. doi:10.1007/s00395-008-0747-7

    Article  PubMed  Google Scholar 

  19. Liu P, Zhou B, Gu D, Zhang L, Han Z (2009) Endothelial progenitor cell therapy in atherosclerosis: a double-edged sword? Ageing Res Rev 8:83–93. doi:10.1016/j.arr.2008.11.002

    Article  CAS  PubMed  Google Scholar 

  20. Luster AD (1998) Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–445. doi:10.1056/NEJM199802123380706

    Article  CAS  PubMed  Google Scholar 

  21. Lyngbaek S, Schneider M, Hansen JL, Sheikh SP (2007) Cardiac regeneration by resident stem and progenitor cells in the adult heart. Basic Res Cardiol 102:101–114. doi:10.1007/s00395-007-0638-3

    Article  PubMed  Google Scholar 

  22. Oerlemans MI, Goumans MJ, van Middelaar B, Clevers H, Doevendans PA, Sluijter JP (2010) Active Wnt signaling in response to cardiac injury. Basic Res Cardiol 105:631–641. doi:10.1007/s00395-010-0100-9

    Article  CAS  PubMed  Google Scholar 

  23. Orlandi A, Chavakis E, Seeger F, Tjwa M, Zeiher AM, Dimmeler S (2010) Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice. Basic Res Cardiol 105:703–712. doi:10.1007/s00395-010-0109-0

    Article  CAS  PubMed  Google Scholar 

  24. Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9(6):702–712. doi:10.1038/nm0603-702

    Article  CAS  PubMed  Google Scholar 

  25. Rollins BJ (2001) Chemokines and atherosclerosis: what Adam Smith has to say about vascular disease. J Clin Invest 108:1269–1271. doi:10.1172/JCI200114273

    CAS  PubMed  Google Scholar 

  26. Sainz J, Sata M (2007) CXCR4, a key modulator of vascular progenitor cells. Arterioscler Thromb Vasc Biol 27:263–265. doi:10.1161/01.ATV.0000256727.34148.e2

    Article  CAS  PubMed  Google Scholar 

  27. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, REPAIR-AMI Investigators (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221. doi:10.1056/NEJMoa060186

    Article  PubMed  Google Scholar 

  28. Schuh A, Liehn EA, Sasse A, Hristov M, Sobota R, Kelm M, Merx MW, Weber C (2008) Transplantation of endothelial progenitor cells improves neovascularization and left ventricular function after myocardial infarction in a rat model. Basic Res Cardiol 103:69–77. doi:10.1007/s00395-007-0685-9

    Article  PubMed  Google Scholar 

  29. Seeger FH, Sedding D, Langheinrich AC, Haendeler J, Zeiher AM, Dimmeler S (2010) Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol 105:389–397. doi:10.1007/s00395-009-0072-9

    Article  CAS  PubMed  Google Scholar 

  30. Spring H, Schüler T, Arnold B, Hämmerling GJ, Ganss R (2005) Chemokines direct endothelial progenitors into tumor neovessels. Proc Natl Acad.Sci USA 102:18111–18116. doi:10.1073/pnas.0507158102

    Article  CAS  PubMed  Google Scholar 

  31. Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, Tan H, Pan X, Wu Z (2009) Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol 104:42–49. doi:10.1007/s00395-008-0738-8

    Article  CAS  PubMed  Google Scholar 

  32. Urbich C, Dimmeler S (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95:343–353. doi:10.1161/01.RES.0000137877.89448.78

    Article  CAS  PubMed  Google Scholar 

  33. Walcher D, Vasic D, Heinz P, Bach H, Durst R, Hausauer A, Hombach V, Marx N (2010) LXR activation inhibits chemokine-induced CD4-positive lymphocyte migration. Basic Res Cardiol 105:487–494. doi:10.1007/s00395-010-0092-5

    Article  CAS  PubMed  Google Scholar 

  34. Walenta K, Friedrich EB, Sehnert F, Werner N, Nickenig G (2005) In vitro differentiation characteristics of cultured human mononuclear cells-implications for endothelial progenitor cell biology. Biochem Biophys Res Commun 333:476–482. doi:10.1016/j.bbrc.2005.05.153

    Article  CAS  PubMed  Google Scholar 

  35. Walenta K, Werner C, Böhm M, Friedrich EB (2010) Promises and pitfalls of endothelial progenitor cells in cardiovascular disease. Stem Cells (in review)

  36. Werner C, Böhm M, Friedrich EB (2008) Role of integrin-linked kinase for functional capacity of endothelial progenitor cells in patients with stable coronary artery disease. Biochem Biophys Res Commun 377:331–336. doi:10.1016/j.bbrc.2008.09.081

    Article  CAS  PubMed  Google Scholar 

  37. Werner N, Nickenig N (2006) Clinical and therapeutical implications of EPC biology in atherosclerosis. J Cell Mol Med 2006:318–332. doi:10.1111/j.1582-4934.2006.tb00402.x

    Article  Google Scholar 

  38. Weber C, Schober A, Zernecke A (2004) Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arterioscler Thromb Vasc Biol 24:1997–2008. doi:10.1161/01.ATV.0000142812.03840.6f

    Article  CAS  PubMed  Google Scholar 

  39. Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T (2003) Stromal cell-derived factor 1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107:1322–1328. doi:10.1161/01.CIR.0000055313.77510.22

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (KFO 196) and a HOMFOR grant of the University of the Saarland. The excellent technical work of Claudia Schormann is greatly appreciated.

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No conflicts of interest to disclose.

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Authors and Affiliations

  1. Klinik für Innere Medizin III (Kardiologie, Angiologie, Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, 66421, Homburg/Saar, Germany

    Katrin L. H. Walenta, Stephanie Bettink, Michael Böhm & Erik B. Friedrich

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  1. Katrin L. H. Walenta
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  4. Erik B. Friedrich
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Correspondence to Katrin L. H. Walenta.

Electronic supplementary material

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395_2010_142_MOESM1_ESM.pdf

Supplemental Fig. 1. CD34–/CD133+/VEGFR-2+ progenitor cells are precursors of CD34+/CD133+/VEGFR-2+ EPC. Peripheral blood mononuclear cells were isolated from healthy human volunteers by density gradient centrifugation. CD133+ cells were bead-purified and stained with the indicated fluorescently tagged antibodies or the corresponding isotype-matched control (IC) for FACS analysis. Importantly, both, CD34−/CD133+ and the CD34+/CD133+ EPC-subsets are characterized by expression of VEGFR2. (PDF 26 kb)

395_2010_142_MOESM2_ESM.pdf

Supplemental Fig. 2. Representative FACS analysis of propidium iodide/annexin V staining of CD34–/CD133+/VEGFR-2+ EPCs. Propidium iodide− and AnnexinV− negative cell are viable cells (bottom left), Propidium iodide+and AnnexinV+ show dead cells and propidium iodide− and AnnexinV+ represent apoptotic cells. (PDF 686 kb)

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Walenta, K.L.H., Bettink, S., Böhm, M. et al. Differential chemokine receptor expression regulates functional specialization of endothelial progenitor cell subpopulations. Basic Res Cardiol 106, 299–305 (2011). https://doi.org/10.1007/s00395-010-0142-z

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  • DOI: https://doi.org/10.1007/s00395-010-0142-z

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