Sphingosine-1-Phosphate and Chemokines in the Control of Osteoclast Precursors Migration Visualized by Intravital Multiphoton Microscopy

2012 ◽  
pp. 73-79
Author(s):  
Junichi Kikuta ◽  
Atsuko Kubo ◽  
Masaru Ishii
Keyword(s):  
Multiphoton Microscopy ◽  
Osteoclast Precursors ◽  
Sphingosine 1 Phosphate

The Role of Sphingosine-1-Phosphate (S1P) in Thrombopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-54-SCI-54
Author(s):  
Steffen Massberg
Keyword(s):  
Conflicts Of Interest ◽  
Multiphoton Microscopy ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Time Loss ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Abstract Human megakaryocytes (MKs) release trillions of platelets each day into the circulation to maintain normal homeostatic platelet levels. However, the signals that control platelet biogenesis in vivo remain incompletely understood. We have recently identified that extracellular sphingosine 1-phosphate (S1P) plays a key role in thrombopoiesis. Using conditional mutants and intravital multiphoton microscopy, we demonstrate that the lipid mediator S1P serves as a critical directional cue guiding the elongation of megakaryocytic proplatelet (PP) extensions from the interstitium into bone marrow sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. In addition to its role as an extracellular mediator, S1P can also function as a second messenger within the intracellular compartment. Correspondingly, we have demonstrated that MKs express the S1P-generating enzyme sphingosine kinase 2 (Sphk2). Sphk2 predominantly localizes to the nucleus and is the major source of intracellular S1P in MKs. Loss of Sphk2 significantly reduced intracellular S1P in MKs and downregulated the expression and activity of Src family kinases (SFKs). At the same time, loss of Sphk2 and inhibition of SFK activity resulted in defective intravascular PP shedding, the final stage of thrombopoiesis. Correspondingly, mice lacking Sphk2 in the hematopoietic system display thrombocytopenia. Collectively, our findings uncover a novel function of S1P as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

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

2012 ◽  
Vol 209 (12) ◽  
pp. 2165-2181 ◽  
Author(s):  
Lin Zhang ◽  
Martin Orban ◽  
Michael Lorenz ◽  
Verena Barocke ◽  
Daniel Braun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multiphoton Microscopy ◽  
Therapeutic Options ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Master Regulator ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) 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 a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, 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.

scholarly journals Erratum: Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis

Nature ◽  
2010 ◽  
Vol 465 (7300) ◽  
pp. 966-966 ◽  
Author(s):  
Masaru Ishii ◽  
Jackson G. Egen ◽  
Frederick Klauschen ◽  
Martin Meier-Schellersheim ◽  
Yukihiko Saeki ◽  
...  
Keyword(s):  
Bone Homeostasis ◽  
Osteoclast Precursors ◽  
Sphingosine 1 Phosphate

scholarly journals The role of sphingosine 1-phosphate in migration of osteoclast precursors; an application of intravital two-photon microscopy

2011 ◽  
Vol 31 (5) ◽  
pp. 399-403 ◽  
Author(s):  
Taeko Ishii ◽  
Yutaka Shimazu ◽  
Issei Nishiyama ◽  
Junichi Kikuta ◽  
Masaru Ishii
Keyword(s):  
Two Photon Microscopy ◽  
Two Photon ◽  
Osteoclast Precursors ◽  
Sphingosine 1 Phosphate

scholarly journals Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis

Nature ◽  
2009 ◽  
Vol 458 (7237) ◽  
pp. 524-528 ◽  
Author(s):  
Masaru Ishii ◽  
Jackson G. Egen ◽  
Frederick Klauschen ◽  
Martin Meier-Schellersheim ◽  
Yukihiko Saeki ◽  
...  
Keyword(s):  
Bone Homeostasis ◽  
Osteoclast Precursors ◽  
Sphingosine 1 Phosphate

Real-time differential labeling of blood, interstitium, and lymphatic and single-field analysis of vasculature dynamics in vivo

2012 ◽  
Vol 302 (10) ◽  
pp. C1460-C1468 ◽  
Author(s):  
Gor Sarkisyan ◽  
Stuart M. Cahalan ◽  
Pedro J. Gonzalez-Cabrera ◽  
Nora B. Leaf ◽  
Hugh Rosen
Keyword(s):  
Endothelial Cells ◽  
Real Time ◽  
Multiphoton Microscopy ◽  
Endothelial Permeability ◽  
Field Analysis ◽  
Lymphocyte Trafficking ◽  
Vascular Integrity ◽  
Sphingosine 1 Phosphate ◽  
Single Field

Lymph nodes are highly organized structures specialized for efficient regulation of adaptive immunity. The blood and lymphatic systems within a lymph node play essential roles by providing functionally distinct environments for lymphocyte entry and egress, respectively. Direct imaging and measurement of vascular microenvironments by intravital multiphoton microscopy provide anatomical and mechanistic insights into the essential events of lymphocyte trafficking. Lymphocytes, blood endothelial cells, and lymphatic endothelial cells express sphingosine 1-phosphate receptor 1, a key G protein-coupled receptor regulating cellular egress and a modulator of endothelial permeability. Here we report the development of a differential vascular labeling (DVL) technique in which a single intravenous injection of a fluorescent dextran, in combination with fluorescent semiconductor quantum dot particles, differentially labels multiple blood and lymphatic compartments in a manner dependent on the size of the fluorescent particle used. Thus DVL allows measurement of endothelial integrity in multiple vascular compartments and the affects or pharmacological manipulation in vascular integrity. In addition, this technique allows for real-time observation of lymphocyte trafficking across physiological barriers differentiated by DVL. Last, single-field fluid movement dynamics can be derived, allowing for the simultaneous determination of fluid flow rates in diverse blood and lymphatic compartments.

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