Mechanisms of thrombopoiesis

Megakaryocytes (MKs) expand and differentiate over several days in response to thrombopoietin (Tpo) before releasing innumerable blood platelets. The final steps in platelet assembly and release represent a unique cellular transformation that is orchestrated by a range of transcription factors, signaling molecules, and cytoskeletal elements. Here we review recent advances in the physiology and molecular basis of MK differentiation. Genome-wide approaches, including transcriptional profiling and proteomics, have been used to identify novel platelet products and differentiation markers. The extracellular factors, stromal-derived factor (SDF)-1 chemokine and fibroblast growth factor (FGF)-4 direct MK interactions with the bone marrow stroma and regulate cytokine-independent cell maturation. An abundance of bone marrow MKs induce pathologic states, including excessive bone formation and myelofibrosis, and the basis for these effects is now better appreciated. We review the status of transcription factors that control MK differentiation, with special emphasis on nuclear factor-erythroid 2 (NF-E2) and its two putative target genes, beta 1-tubulin and 3-beta-hydroxysteroid reductase. MKs express steroid receptors and some estrogen ligands, which may constitute an autocrine loop in formation of proplatelets, the cytoplasmic protrusions within which nascent blood platelets are assembled. Finally, we summarize our own studies on cellular and molecular facets of proplatelet formation and place the findings within the context of outstanding questions about mechanisms of thrombopoiesis.