Platelet formation

Abstract

Thrombocytopenia is the underlying cause of a number of major clinical conditions and genetic disorders worldwide. While therapeutic agents that bind and stimulate the thrombopoietin receptor are currently available, the development of drugs that directly stimulate megakaryocytes to generate platelets has lagged behind. To improve the management of thrombocytopenia, we will need to define the cell biological pathways that drive the production of platelets from megakaryocytes. This review integrates the latest research of platelet biogenesis and focuses on the molecular pathways that power and regulate proplatelet production.

Figure 1. Summary of megakaryocyte maturation and platelet production

Hematopoietic stem cells (HSCs) residing next to the endosteal bone surface produce progenitors that migrate to blood vessels at the center of the bone marrow cavity. Upon each division, a single daughter cell leaves the bone to proliferate and differentiate into various possible lineages of which the megakaryocyte is one. An elaborate intracellular program of nuclear amplification and protein production in maturing megakaryocytes precedes the mechanical extension of proplatelet elongations into the sinusoidal blood vessels of the bone marrow. Released proplatelets continue to mature in the vasculature and ultimately release individual platelets from their tips. CMP, common myeloid progenitor; CLP, common lymphoid progenitor; GMP, granulocyte/macrophage progenitor; MKEP, megakaryocyte erythroid progenitor; MPP, multipotent progenitor stem cell; TBA, trabecular bone area. Adapted from Yin et al 2006.

Figure 2. Cytoskeletal mechanisms of proplatelet production and platelet release

A systematic series of events occurs as megakaryocytes transition from immature cells (A) to released platelets (E). (B) Immature megakaryocytes will undergo repeated cycles of nuclear endomitosis for the purpose of supporting organelle synthesis, and dramatic cytoplasmic maturation and expansion. (C) Prior to the onset of proplatelet formation, centrosomes disassemble and microtubules translocate to the cell cortex. A demarcation membrane system that is continuous with the surface membrane of the cell provides a reservoir of membrane for growth of the proplatelet processes. Thick bundles of microtubules fill the shafts and cortex of broad pseudopodia that are subsequently extended by the megakaryocyte. (D) Sliding of overlapping microtubules drives proplatelet elongation as organelles are tracked into proplatelet ends. Proplatelet formation continues to expand throughout the cell while bending and branching amplify existing proplatelet ends. (E) The entire megakaryocyte cytoplasm is converted into a mass of proplatelets, which are released from the cell. As proplatelets elongate, their microtubule bundles twist, bringing opposing bundles in contact, and allowing them to become zipped together in the proplatelet shaft. This forms loops at the ends of the proplatelets where granules and organelles become trapped. Sliding movements by microtubules in the shaft elongate released proplatelets further, and separate the ends from the shaft, mediating platelet release. Adapted from Hartwig et al 2006, and Patel et al 2005.