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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.
Submitted March 17, 2008
Université de Lyon, Lyon, France * Corresponding author; email: maguer{at}lyon.fnclcc.fr.
Activin A, BMP2 and BMP4, three members of the TGF-
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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 TPO, BMP4 is able to induce CD34+ progenitor differentiation into megakaryocytes through all stages. Whereas 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 TPO, 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 TPO uses the BMP4 pathway to induce megakaryopoiesis, while the inverse is not occurring. Finally, we show that TPO 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.
