Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4.
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 (S1P(4)) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P(4)-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 S1P(4) in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P(4) is involved in shaping the terminal differentiation of megakaryocytes.
Golfier
Sven
S
Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Kondo
Shinichi
S
Schulze
Tobias
T
Takeuchi
Tomomi
T
Vassileva
Galya
G
Achtman
Ariel H
AH
Gräler
Markus H
MH
Abbondanzo
Susan J
SJ
Wiekowski
Maria
M
Kremmer
Elisabeth
E
Endo
Yasuhisa
Y
Lira
Sergio A
SA
Bacon
Kevin B
KB
Lipp
Martin
M
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D015139:Blotting, Southern; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013926:Thrombopoietin / Q000097:blood
D040201:Platelet Membrane Glycoprotein IIb; D049349:Receptors, Lysosphingolipid; D013926:Thrombopoietin