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A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis

Zhang, Lin and Orban, Martin and Lorenz, Michael and Barocke, Verena and Braun, Daniel and Urtz, Nicole and Schulz, Christian and Proia, Richard L. and von Bruehl, Marie-Luise and Graf, Thomas and Bolz, Steffen-Sebastian and Montanez, Eloi and Prinz, Marco and Müller, Alexandra and Billich, Andreas and Sixt, Michael and von Andrian, Ulrich H. and Junt, Tobias and Massberg, Steffen and Tirniceriu, Anca and Gaertner, Florian and von Baumgarten, Louisa and Faessler, Reinhard (2012) A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis. Journal of Experimental Medicine, 209 (12). pp. 2165-2181. ISSN 0022-1007

Abstract

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes
(MKs). MKs extend transendothelial proplatelet extensions into BM sinusoids and shed
new platelets into the blood. The mechanisms that control platelet generation remain
incompletely understood. Using conditional mutants and intravital multiphoton
microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves
as critical directional cue guiding the elongation of megakaryocytic proplatelet
extensions from the interstitium into BM sinusoids and triggering the subsequent
shedding of proplatelets into the blood. Correspondingly, mice lacking the S1P receptor
S1pr1 develop severe thrombocytopenia due to both formation of aberrant
extravascular proplatelets and defective intravascular proplatelet shedding. By contrast,
activation of S1pr1 signaling leads to the prompt release of new platelets into the
circulating blood. Taken together, our findings uncover a novel function of the
S1P/S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new
therapeutic options for patients with thrombocytopenia.

Item Type: Article
Related URLs:
Keywords: platelets, S1P, megakaryocytes, thrombopoiesis, intravital 2-photon microscopy
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2282

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