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

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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.

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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.).

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Authors

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)

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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

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