Don't you forget about me(gakaryocytes).

Platelets, small, anucleate cell fragments, derive from large precursor cells, megakaryocytes (MKs), that reside in the bone marrow. MKs emerge from hematopoietic stem cells in a complex differentiation process that involves cytoplasmic maturation, including the formation of the demarcation membrane system, and polyploidization. The main function of MKs is the generation of platelets, which predominantly occurs through the release of long, microtubule-rich proplatelets into vessel sinusoids. However, the idea of a one-dimensional role of MKs as platelet precursors is currently being questioned due to advances in high resolution microscopy and single-cell Omics. On the one hand, recent findings suggest that proplatelet formation from bone marrow-derived MKs is not the only mechanism of platelet production, but that it might also occur through budding of the plasma membrane and in distant organs like lung or liver. On the other hand, novel evidence suggests that MKs do not only maintain physiological platelet levels but further contribute to bone marrow homeostasis through the release of extracellular vesicles or cytokines such as transforming growth factor β1 or platelet factor 4. The notion of multitasking MKs was reinforced in recent studies using single cell RNA sequencing approaches on MKs derived from adult and fetal bone marrow and lungs, leading to the identification of different MK subsets that appear to exhibit immunomodulatory or secretory roles. In the following, novel insights into the mechanisms leading to proplatelet formation in vitro and in vivo will be reviewed and the hypothesis of megakaryocytes as immunoregulatory cells will be critically discussed.