Paracrine regulation of megakaryo/thrombopoiesis by macrophages.

D'ATRI LP; POZNER RG; NAHMOD KA; LANDONI VI ; ISTURIZ M; NEGROTTO S; SCHATTNER M

EXPERIMENTAL HEMATOLOGY

ELSEVIER SCIENCE INC

Año: 2011 vol. 39 p. 763 - 772

0301-472X

Objective. Megakaryo/thrombopoiesis is a complex process regulated by multiple signalsprovided by the bone marrow microenvironment. Because macrophages are relevant componentsof the bone marrow stroma and their activation induces an upregulation of moleculesthat can regulate hematopoiesis, we analyzed the impact of these cells on the control ofmegakaryocyte development and platelet biogenesis.Materials and Methods. The different stages of megakaryo/thrombopoiesis were analyzed byflow cytometry using an in vitro model of human cord blood CD34+ cells stimulated withthrombopoietin in either a transwell system or conditioned media from monocyte-derivedmacrophages isolated from peripheral blood. Cytokines secreted from macrophages werecharacterized by protein array and enzyme-linked immunosorbent assay.Results. Resting macrophages released soluble factors that promoted megakaryocyte growth,cell ploidy, a size increase, proplatelet production, and platelet release. Lipopolysaccharidestimulation triggered the secretion of cytokines that exerted opposite effects together witha dramatic switch of CD34+ commitment to the megakaryocytic lineage toward the myeloidlineage. Neutralization of interleukin-8 released by stimulated macrophages partially reversedthe inhibition of megakaryocyte growth. Activation of nuclear factor kB had a major role inthe synthesis of molecules involved in the megakaryocyte inhibition mediated bylipopolysaccharide-stimulated macrophages.Conclusions. Our study extends our understanding about the role of the bone marrowmicroenvironment in the regulation of megakaryo/thrombopoiesis by showing that solublefactors derived from macrophages positively or negatively control megakaryocyte growth,differentiation, maturation, and their ability to produce platelets.