Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P₄

Abstract

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.

Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

“…38 Another S1P receptor subtype, S1PR1 , plays an important role in regulating immune cell function and lymphocyte trafficking by regulating egress of lymphocytes from bone marrow and lymphoid tissues; 39–41 however, much less is known about the function of S1PR4. S1PR4 is expressed on hematopoietic and lymphoid cells and has been implicated in terminal megakaryocyte differentiation to platelets, 42 and the regulation of dendritic cell function and T(H)17-cell 43 and plasmacytoid dendritic cell 44 differentiation. S1PR4 is highly expressed in neutrophils and lymphocytes.…”

Sphingosine 1-phosphate in coagulation and inflammation

“…Recently, S1P 4 -deficient mice were reported, showing that S1P 4 played a role in shaping the terminal differentiation of megakaryocytes and proplatelet development [90]. …”

Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype

“…Notably, the application of S1P 4 –R antagonist might be exploited for inhibiting potentially detrimental reactive thrombocytosis, whereas S1P 4 –R agonists represent a potential therapeutic approach for stimulating platelet repopulation after thrombocytopenia. 20 …”