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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3154-3163.
Prepublished online as a Blood First Edition Paper on July 29, 2008; DOI 10.1182/blood-2008-03-145326.

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HEMATOPOIESIS AND STEM CELLS

BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling

Sandrine Jeanpierre15, Franck Emmanuel Nicolini6, Bastien Kaniewski15, Charles Dumontet1,3,5, Ruth Rimokh13,5, Alain Puisieux15, and Véronique Maguer-Satta13,5

1 Université de Lyon, Lyon; 2 Université de Lyon 1, Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Lyon; 3 Inserm U 590, Lyon; 4 Centre Léon Bérard, Lyon; 5 IFR62, Lyon; and 6 Department d'Hématologie, Hôpital Edouard Herriot, Lyon, France

Activin A, BMP2, and BMP4, 3 members of the transforming growth factor-β family, are involved in the regulation of hematopoiesis. Here, we explored the role of these molecules in human megakaryopoiesis using an in vitro serum-free assay. Our results highlight for the first time that, in the absence of thrombopoietin, BMP4 is able to induce CD34+ progenitor differentiation into megakaryocytes through all stages. Although we have previously shown that activin A and BMP2 are involved in erythropoietic commitment, these molecules have no effect on human megakaryopoietic engagement and differentiation. Using signaling pathway-specific inhibitors, we show that BMP4, like thrombopoietin, exerts its effects on human megakaryopoiesis through the JAK/STAT and mTor pathways. Inhibition of the BMP signaling pathway with blocking antibodies, natural soluble inhibitors (FLRG or follistatin), or soluble BMP receptors reveals that thrombopoietin uses the BMP4 pathway to induce megakaryopoiesis, whereas the inverse is not occurring. Finally, we show that thrombopoietin up-regulates the BMP4 autocrine loop in megakaryocytic progenitors by inducing their production of BMP4 and up-regulating BMP receptor expression. In summary, this work indicates that BMP4 plays an important role in the control of human megakaryopoiesis.


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