Skip to main content

Advertisement

SpringerLink
Log in

PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1)

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Platelets have been regarded as static cells that do not move once they adhere to a matrix. The present study explored, whether platelets are able to migrate. In contrast to the current opinion, we found that platelets were mobile, able to migrate over a surface, and transmigrate through a transwell membrane and endothelium toward a source of stromal cell-derived factor 1 (SDF-1). Platelet migration was stimulated by SDF-1, which led to the downstream activation and phosphorylation of Wiskott–Aldrich syndrome protein. SDF-1 signaling and subsequent platelet migration could be inhibited by CXCR4-receptor blocker AMD3100, pertussis toxin, inhibition of phosphoinositol 3-kinase (PI3 kinase) with LY294002 or wortmannin, and disruption of actin polymerization with cytochalasin B. The potential of platelets to migrate in an SDF-1-mediated fashion may redefine the role of platelets in the pathophysiology of vascular inflammation, subsequent atherosclerotic degeneration, and vascular regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Berger G, Hartwell DW, Wagner DD (1998) P-selectin and platelet clearance. Blood 92:4446–4452

    CAS  PubMed  Google Scholar 

  2. Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, Yost CC, Rubner FJ, Albertine KH, Swoboda KJ et al (2005) Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122:379–391

    Article  CAS  PubMed  Google Scholar 

  3. Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, Weyrich AS (2001) Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 154:485–490

    Article  CAS  PubMed  Google Scholar 

  4. Lindemann S, Tolley ND, Eyre JR, Kraiss LW, Mahoney TM, Weyrich AS (2001) Integrins regulate the intracellular distribution of eukaryotic initiation factor 4E in platelets. A checkpoint for translational control. J Biol Chem 276:33947–33951

    Article  CAS  PubMed  Google Scholar 

  5. Jakab M, Ritter M (2006) Cell volume regulatory ion transport in the regulation of cell migration. Contrib Nephrol 152:161–180

    Article  CAS  PubMed  Google Scholar 

  6. Papakonstanti EA, Stournaras C (2008) Cell responses regulated by early reorganization of actin cytoskeleton. FEBS Lett 582:2120–2127

    Article  CAS  PubMed  Google Scholar 

  7. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709

    Article  CAS  PubMed  Google Scholar 

  8. Schwab A, Nechyporuk-Zloy V, Fabian A, Stock C (2007) Cells move when ions and water flow. Pflugers Arch 453:421–432

    Article  CAS  PubMed  Google Scholar 

  9. Lewin J (2002) The evolution of mammalian platelets. In: Michelson ED (ed) platelets. Academic, San Diego, pp 3–17

    Google Scholar 

  10. Kakoma I, Carson CA, Ristic M, Stephenson EM, Hildebrandt PK, Huxsoll DL (1978) Platelet migration inhibition as an indicator of immunologically mediated target cell injury in canine ehrlichiosis. Infect Immun 20:242–247

    CAS  PubMed  Google Scholar 

  11. Valone FH, Austen KF, Goetzl EJ (1974) Modulation of the random migration of human platelets. J Clin Invest 54:1100–1106

    Article  CAS  PubMed  Google Scholar 

  12. Czapiga M, Gao JL, Kirk A, Lekstrom-Himes J (2005) Human platelets exhibit chemotaxis using functional N-formyl peptide receptors. Exp Hematol 33:73–84

    Article  CAS  PubMed  Google Scholar 

  13. Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM (1998) Platelets exit venules by a transcellular pathway at sites of F-met peptide-induced acute inflammation in guinea pigs. Int Arch Allergy Immunol 116:188–195

    Article  CAS  PubMed  Google Scholar 

  14. Pitchford SC, Momi S, Baglioni S, Casali L, Giannini S, Rossi R, Page CP, Gresele P (2008) Allergen induces the migration of platelets to lung tissue in allergic asthma. Am J Respir Crit Care Med 177:604–612

    Article  CAS  PubMed  Google Scholar 

  15. Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD (2000) The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res 86:131–138

    CAS  PubMed  Google Scholar 

  16. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184:1101–1109

    Article  CAS  PubMed  Google Scholar 

  17. Hamada T, Mohle R, Hesselgesser J, Hoxie J, Nachman RL, Moore MA, Rafii S (1998) Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med 188:539–548

    Article  CAS  PubMed  Google Scholar 

  18. Phillips R, Ager A (2002) Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol 32:837–847

    Article  CAS  PubMed  Google Scholar 

  19. Zheng H, Fu G, Dai T, Huang H (2007) Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol 50:274–280

    Article  CAS  PubMed  Google Scholar 

  20. Clemetson KJ, Clemetson JM, Proudfoot AE, Power CA, Baggiolini M, Wells TN (2000) Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood 96:4046–4054

    CAS  PubMed  Google Scholar 

  21. Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, Bigalke B, Mueller I, Schumm M, Schaefer I et al (2008) Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 117:206–215

    Article  CAS  PubMed  Google Scholar 

  22. Haddad E, Zugaza JL, Louache F, Debili N, Crouin C, Schwarz K, Fischer A, Vainchenker W, Bertoglio J (2001) The interaction between Cdc42 and WASP is required for SDF-1-induced T-lymphocyte chemotaxis. Blood 97:33–38

    Article  CAS  PubMed  Google Scholar 

  23. Okabe S, Fukuda S, Broxmeyer HE (2002) Activation of Wiskott–Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in a T-lymphocyte line. Exp Hematol 30:761–766

    Article  CAS  PubMed  Google Scholar 

  24. Higgs HN, Pollard TD (1999) Regulation of actin polymerization by Arp2/3 complex and WASp/Scar proteins. J Biol Chem 274:32531–32534

    Article  CAS  PubMed  Google Scholar 

  25. Thrasher AJ (2002) WASp in immune-system organization and function. Nat Rev Immunol 2:635–646

    Article  CAS  PubMed  Google Scholar 

  26. Fernandis AZ, Prasad A, Band H, Klosel R, Ganju RK (2004) Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene 23:157–167

    Article  CAS  PubMed  Google Scholar 

  27. Primo L, di Blasio L, Roca C, Droetto S, Piva R, Schaffhausen B, Bussolino F (2007) Essential role of PDK1 in regulating endothelial cell migration. J Cell Biol 176:1035–1047

    Article  CAS  PubMed  Google Scholar 

  28. Hartmann TN, Grabovsky V, Pasvolsky R, Shulman Z, Buss EC, Spiegel A, Nagler A, Lapidot T, Thelen M, Alon R (2008) A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J Leukoc Biol 84:1130–1140

    Article  CAS  PubMed  Google Scholar 

  29. Hatse S, Princen K, Bridger G, De Clercq E, Schols D (2002) Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett 527:255–262

    Article  CAS  PubMed  Google Scholar 

  30. Ui M (1984) Islet-activating protein, pertussis toxin: a probe for functions of the inhibitory guanine nucleotide regulatory component of adenylate cyclase. Trends Pharmacol Sci 5:277–279

    Article  CAS  Google Scholar 

  31. Schäfer A, Schulz C, Eigenthaler M, Fraccarollo D, Kobsar A, Gawaz M, Ertl G, Walter U, Bauersachs J (2004) Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion. Blood 103:407–12

    Article  PubMed  Google Scholar 

  32. Banga HS, Walker RK, Winberry LK, Rittenhouse SE (1987) Pertussis toxin can activate human platelets. Comparative effects of holotoxin and its ADP-ribosylating S1 subunit. J Biol Chem 262:14871–4

    CAS  PubMed  Google Scholar 

  33. Choudhury GG, Karamitsos C, Hernandez J, Gentilini A, Bardgette J, Abboud HE (1997) PI-3-kinase and MAPK regulate mesangial cell proliferation and migration in response to PDGF. Am J Physiol 273:F931–F938

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Jadwiga Kwiatkowska, Christina Neff, and Birgit Fehrenbacher for providing outstanding technical assistance and Uwe Renzland for the help in preparing and formatting the movies. This study was supported by the Deutsche Forschungsgemeinschaft (Li 849/3-1 to S.L., SFB-TR19 TP B8 to K.S., M.G., and S.L.), the fortüne programme (1934-0-0 to O.B.) and the Karl-Kuhn-Stiftung (to S.L.).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Abteilung III, Kardiologie und Kreislauferkrankungen, Medizinische Klinik, Universitätsklinikum Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany

    Bjoern F. Kraemer, Oliver Borst, Tanja Schoenberger, Benjamin Urban, Elena Ninci, Peter Seizer, Christine Schmidt, Boris Bigalke, Miriam Koch, Karin Daub, Laura Schwanitz, Konstantinos Stellos, Meinrad Gawaz & Stephan Lindemann

  2. Physiologisches Institut der Eberhard-Karls-Universität Tübingen, Gmelinstrasse 5, 72076, Tübingen, Germany

    Oliver Borst, Eva-Maria Gehring & Florian Lang

  3. Klinik für Herz- und thorakale Gefäßchirurgie der Philipps-Universität-Marburg, Baldingerstrasse 1, Marburg, 35037, Germany

    Ivo Martinovic

  4. Naturwissenschaftliches und Medizinisches Institut der Universität Tübingen, Markwiesenstrasse 55, Reutlingen, 72770, Germany

    Tobias Merz

  5. Abteilung Neurodegenerative Erkrankungen, HERTIE-Institut für Klinische Hirnforschung, Hoppe-Seyler-Strasse 3, Tübingen, 72076, Germany

    Fabienne Fiesel

  6. Hautklinik, Universitätshautklinik Tübingen, Liebermeisterstrasse 25, Tübingen, 72076, Germany

    Martin Schaller

Authors
  1. Bjoern F. Kraemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Borst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva-Maria Gehring
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tanja Schoenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin Urban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Ninci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Seizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christine Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Boris Bigalke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Miriam Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ivo Martinovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Karin Daub
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tobias Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Laura Schwanitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Konstantinos Stellos
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Fabienne Fiesel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Martin Schaller
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Florian Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Meinrad Gawaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Stephan Lindemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Florian Lang or Meinrad Gawaz.

Additional information

Bjoern F. Kraemer and Oliver Borst contributed equally to this work and share first authorship.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(recording time: 180 min, 30 frames/hour; replay 10 frames/second) Platelet chemotaxis toward a source of SDF-1. (Representative movie out of three experiments) (AVI 4567 kb)

(recording time: 180 min, 30 frames/hour; replay 10 frames/second) Control experiment to Movie I without chemokine at the target source. (Representative movie out of three experiments) (AVI 5222 kb)

(recording time: 57 min, six frames/minute; replay 20 frames/second) Example of a platelet that migrates toward the source of SDF-1 in the platelet cohort shown in Movie I. SDF-1 source at the top of the image (AVI 1091 kb)

(recording time: 85 min, 6 frames/minute; replay 20 frames/second) Platelet migration on a fibrinogen matrix. (Representative movie out of three experiments) (AVI 5968 kb)

(recording time: 20 min, six frames/minute; replay 20 frames/second) Inhibition of platelet migration with cytochalasin B. (Representative movie out of three experiments) (AVI 2188 kb)

Supplemental Figure 1

SDF-1 mediated Platelet Transmigration. Absolute numbers of transmigrating platelets towards a source of SDF-1 (supplemental to Figure 3A) (PDF 10 kb)

Supplemental Figure 2

SDF-1-mediated transmigration of platelets through activated and unactivated endothelium, absolute numbers and percentage of platelets transmigrating (%), supplemental to Fig. 3b (PDF 8 kb)

Supplemental Figure 3

Table summary of SDF-1 mediated platelet transmigration with and without endothelium, absolute numbers and percentage of transmigrating platelets (%) (PDF 7 kb)

Supplemental Figure 4

Absolute numbers of platelet transmigration and inhibition of SDF-1-induced platelet transmigration by blockers of the CXCR4-receptor (AMD3100), G-protein (PTX) and PI3 kinase (wortmannin; LY 294002), supplemental to Fig. 4a (PDF 8 kb)

Supplemental Figure 5

Role of platelet activation for transmigrational activity. Platelet baseline transmigration is slightly increased with thrombin activation which does not meet the robust increase in transmigration with SDF-1 alone. On the contrary, excessive pre-activation of platelets with thrombin appears to negatively interfere with the SDF-1 effect compared to SDF-1 alone (PDF 7 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kraemer, B.F., Borst, O., Gehring, EM. et al. PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). J Mol Med 88, 1277–1288 (2010). https://doi.org/10.1007/s00109-010-0680-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-010-0680-8

Keywords

Search

Navigation