Signalling Pathways Regulating Platelet Biogenesis

Platelet biogenesis is a complex process controlled by a combination of cell-extrinsic and cell-intrinsic factors. Cell-extrinsic factors include cytokines and growth factors, chemokines, extracellular matrix proteins, cell-cell interactions and shear forces within the bone marrow milieu that act on megakaryocytes. Cell-intrinsic factors include receptors and associated signalling pathways, cytoskeletal structures, lipid and cation concentrations found within megakaryocytes. Collectively, these two sets of factors control the differentiation, proliferation and survival of megakaryocytes and produce platelets. Recent discoveries have greatly increased our understanding of the molecular mechanisms controlling platelet biogenesis; however, major gaps remain in our knowledge regarding signalling events regulating the transition from megakaryopoiesis to thrombopoiesis, the triggering of proplatelet formation and platelet release and the inhibition of activation signals within megakaryocytes during the course of platelet biogenesis. A major step will be to map all of the signalling networks within megakaryocytes and elucidate their interconnectedness. In this chapter, we describe some of the major signalling pathways that regulate platelet biogenesis, novel modes of regulation and inhibitory mechanisms that prevent uncontrolled megakaryocyte and platelet activation. We also highlight key questions that remain to be addressed and propose potential mechanisms. It is only through a comprehensive understanding of how platelet biogenesis is regulated that we will be able to identify key signalling nodes that can be targeted to modulate platelet homeostasis in health and disease.