Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P

• Published in: The FASEB journal Vol. 24; no. 12; pp. 4701 - 4710
• Main Authors: Golfier, Sven, Kondo, Shinichi, Schulze, Tobias, Takeuchi, Tomomi, Vassileva, Galya, Achtman, Ariel H, Gräler, Markus H, Abbondanzo, Susan J, Wiekowski, Maria, Kremmer, Elisabeth, Endo, Yasuhisa, Lira, Sergio A, Bacon, Kevin B, Lipp, Martin
• Format: Journal Article
• Language: English
• Published: The Federation of American Societies for Experimental Biology 01.12.2010
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-141473

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphingosine 1-phosphate receptor 4 (S1P₄) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P₄-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4⁻/⁻ mice. Remarkably, overexpression and stimulation of S1P₄ in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P₄ is involved in shaping the terminal differentiation of megakaryocytes.--Golfier, S., Kondo, S., Schulze, T., Takeuchi, T., Vassileva, G., Achtman, A. H., Gräler, M. H., Abbondanzo, S. J., Wiekowski, M., Kremmer, E., Endo, Y., Lira, S. A., Bacon, K. B., Lipp, M. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P₄.