Megakaryocyte rupture for acute platelet needs

Abstract

Circulating platelets were thought to arise solely from the protrusion and fragmentation of megakaryocyte cytoplasm. Now, Nishimura et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201410052) show that platelet release from megakaryocytes can be induced by interleukin-1α (IL-1α) via a new rupture mechanism, which yields higher platelet numbers, occurs independently of the key regulator of megakaryopoiesis thrombopoietin, and may occur during situations of acute platelet need.

Figure 1.

Platelet production in normal physiology and upon acute platelet needs. In normal physiology (left), platelets are continuously produced by megakaryocytes via the classical process of proplatelet formation. Under these conditions, thrombopoietin (Thpo) drives megakaryopoiesis by signaling through its receptor c-Mpl, but Thpo is dispensable for proplatelet formation, which is a cell-autonomous process and presumably regulated by the vascular niche. Inhibition of Caspase-3 and a well-organized orchestration of microtubule dynamics (green) are prerequisites for proper proplatelet formation and protrusion into bone marrow sinusoids, where preplatelets are released and further mature within the circulation. Proplatelet formation is a rather slow process with low yields of platelets per period of time but is sufficient to compensate for the continuous loss of aged platelets. Under conditions of increased platelet loss or consumption (right), e.g., as a result of excessive blood loss or in the setting of infection/inflammation, this mechanism might not be sufficient to ensure appropriate platelet supply. Under these conditions, interleukin-1α (IL-1α) levels increase rapidly and trigger rupture-type platelet formation via its receptor IL-1R1 on megakaryocytes. IL-1α signaling leads to a deregulated expression and organization of β1-tubulin (green) as well as to the activation of Caspase-3, which in turn leads to a reduction of megakaryocyte membrane stiffness. Together, these processes lead to the formation of multiple membrane blebs that are predominantly released into bone marrow sinusoids to quickly replenish platelet numbers.