Editorial

As we are writing this editorial, the world’s worst pandemic in over a hundred years is progressing and a quarter of the world is on lock-down. COVID-19 has already claimed the lives of tens of thousands of people and is predicted to cause a catastrophic worldwide economic downturn. The pace of progress in science and medicine over the last 100 years has been staggering, from understanding the truly small – such as viruses, bacteria and immunomodulatory proteins, DNA, and protein signaling – and also enabling ‘big data’ studies – of population genomics, public health impacts of mass vaccination and large-scale production of therapeutic antibodies. As the COVID-19 crisis unfolds, scientists, engineers, industrialists, and governments must now race together to solve issues of developing, producing, and distributing new testing platforms, new treatments, new pipelines for the production of hardware, and new strategies for dealing with the social consequences of isolation, etc. The world will be a different place after COVID-19 in part because of the solutions we will find to these issues, but hopefully new bridges will be built between STEM disciplines that can continue to progress science more rapidly in other areas.

This issue of Platelets highlights the considerable recent progress made in understanding megakaryocyte biology. We are now able to explore the transcriptome, genome, and epigenome megakaryocytes and their progenitors at single-cell level, measure subtle differences in function, and record how these cells behave with super-resolution, single-molecule imaging. We have reached the point where large-scale production of megakaryocytes and platelets in vitro for clinical use is now a concrete venture rather than just a dream. However, questions remain, sometimes creating passionate controversy. In this issue, we cover some of those remaining questions and controversies.

Davenport et al., focus on developmental changes in megakaryopoiesis over human ontogeny. The last 10 years have shed critical light on the differences between prenatal, neonatal, and adult megakaryocytes, which is summarized in this paper with a particular focus on relevance to pediatric health and diseases. This illustrates how our “natural” approaches to managing thrombocytopenia in adult patients may not be right in the pediatric setting, and how the treatment of platelet disorders affecting younger patients such as Down-syndrome Transient Myeloproliferative Disorder benefit from a deep understanding of their precise developmental biology.

Vainchenker and Raslova look into megakaryocyte polyploidization. This rare biological process has been a subject of fascination for a long time. We routinely measure polyploidization as a parameter of megakaryocyte maturity. However, the molecular mechanisms that regulate polyploidization have only just started to be understood. Many questions remain: what does it do to megakaryocyte function? Is it truly necessary? Is transcription/translation of DNA in distinct megakaryocyte nuclear lobes differentially regulated? The importance of these questions is illustrated by the dramatic changes in polyploidization between fetal, cord blood, and adult megakaryocytes as well as murine and human cells. In addition, in vitro cultured megakaryocytes never achieve the very high ploidy observed in megakaryocytes differentiated in their “natural” context, suggesting cell-extrinsic influences on polyploidization mechanics.

Emperipolesis, just like ploidization, has been noted for a long time on bone marrow sections or smears with links to certain pathologies, although remained just a biological curiosity. Cunin et al. discuss the interesting concept that emperipolesis may be a biological phenomenon that has functional consequences on the platelet progeny of those megakaryocytes that have “swallowed” neutrophils.

Recent leaps forward in imaging capabilities have allowed recording of events such as platelet release “in situ” within the bone marrow, or indeed other organs such as the lungs. In vitro platelet release is several orders of magnitude less efficient than what occurs in vivo. Controversy still rages in the field not only with regards to how platelets are released: proplatelet vs fragmentation (or both!), but also where bone marrow vs. lung (or both!) with high-impact publications supporting each of these schools of thought. Abbonante et al. review our current knowledge of the mechanism of platelet release but crucially look at what aspects of the niche are permissive for efficient platelet release in vivo. The implications of this for platelet manufacturing are discussed. In addition, Mookerjee et al. look at producing platelets in vitro for clinical application, where it is hoped that the recent progress will soon enable first-in-human studies to take place.

This collection of articles illustrates both the immense progress and the unanswered questions in the field of megakaryocyte biology. The remaining challenges present an opportunity and motivation to further advance the field and enable translation of cutting-edge science to the clinic. This is important for a number of reasons. Firstly, because of the key ‘traditional’ role of platelets in thromboembolic disease, one of the major causes of morbidity and mortality worldwide. Secondly, platelet transfusions are the second most commonly used blood product and the one that is most precarious given its short shelf-life. And finally, and perhaps most topically, additional roles for platelets and megakaryocytes as mediators of immunity including in viral infections are increasingly recognized. Achieving the next steps forward in our understanding of megakaryocyte biology may therefore have a significant impact on global health.