Platelets are tiny cells that are necessary for hemostasis; they aggregate at sites of injury to prevent blood loss. Platelets are derived from megakaryocytes. Unlike platelets, megakaryocytes are enormous cells that reside in the bone marrow and elsewhere during development and undergo highly complex processes to generate platelets. The better we can understand these processes, the closer we will come to being able to generate safe sources of platelets for therapeutic purposes.
Why do we need to generate platelets when they are already available via donor transfusions? As outlined by Sim et al, alternative sources of platelets are needed because of transfusion-related side effects, donations that do not keep up with demands, and their usefulness in preventing injury and in treating thrombocytopenia after blood loss, chemotherapy, radiation, sepsis, or other situations in which platelets are consumed. A distinct need is the promise of curing inborn megakaryocyte/platelet diseases or targeted delivery of drugs via gene therapy as described by Wilcox.
The challenges of creating alternative sources of megakaryocytes and platelets are many but are not insurmountable, and much progress has been made. Major challenges still exist in producing not only the required numbers of platelets but also platelets that are responsive to agonists and that display enough of a repertoire of platelet-activation responses to be maximally beneficial.
These topics, along with challenges and potential solutions, are discussed in the following commissioned review series on “Megakaryocytes to platelets in health and disease”:
Xiuli Sim, Mortimer Poncz, Paul Gadue, and Deborah L. French, “Understanding platelet generation from megakaryocytes: implications for in vitro–derived platelets”
Koji Eto and Shinji Kunishima, “Linkage between the mechanisms of thrombocytopenia and thrombopoiesis”
Carolien M. Woolthuis and Christopher Y. Park, “Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage”
Elisa Bianchi, Ruggiero Norfo, Valentina Pennucci, Roberta Zini, and Rossella Manfredini, “Genomic landscape of megakaryocytopoiesis and platelet function defects”
David A. Wilcox, “Megakaryocyte- and megakaryocyte precursor–related gene therapies”
The promise and challenges of stem cell differentiation are discussed by Sim et al. Although CCD34+ human progenitor stem cells fall short as an ideal starting source, because they must be continually resupplied, human pluripotent stem cells (PSCs), which include embryonic stem cells and induced PSCs, offer more promise as an easily renewable source because they replicate indefinitely and can be genetically manipulated. Challenges still exist however, with regard to the yield, responsiveness, and half-life of the platelets generated by these systems.
To improve platelet production, it is imperative to understand the process from its very early to its latest stages. Several of the reviews in this series examine megakaryopoiesis and thrombopoiesis from different perspectives. Eto and Kunishima summarize classic and newer models of megakaryopoiesis, as well as newly appreciated roles of thrombopoietin and its receptor, Mpl. The roles of other molecules in this process have become apparent, in large part, from studies of familial/genetic defects and targeted approaches. These molecules include cytoskeletal proteins, scaffolding proteins, transcription factors, and more. As such, this review and others provide a treasure trove of ideas on a molecular level for improving megakaryocyte and platelet production for researchers dedicated to this endeavor.
The very earliest stages of megakaryopoiesis and the cells with this potential are not clearly understood, but this knowledge may broaden our approaches to meeting the challenge of efficient platelet production. Woolthuis and Park discuss where commitment can occur and describe how this commitment is not fixed, but flexible, and can be initiated via multiple pathways in a fascinating new model of megakaryopoiesis. Their new model consequently shows possible fast tracks to megakaryocyte production. Gene expression study suggests that hematopoietic stem cells (HSCs) are most closely related to the megakaryocyte/erythrocyte, or “MegE,” lineage. They describe how endothelial and hematopoietic lineages share a precursor, the hemangioblast, and how HSCs may rapidly commit. An interesting and related topic is a summary of recent data on how megakaryocytes contribute to the HSC niche to regulate HSC quiescence.
Bianchi et al discuss the genomic landscape of malignant megakaryocytopoiesis. These diseases are as useful for revealing the normal roles of molecules and processes as are studies of the loss of megakaryopoiesis. These investigators consider a range of regulatory processes, including driver mutations in transcription factors and signaling molecules, epigenetic alterations, microRNAs and noncoding transcripts, and RNA splicing. They further discuss how insight from malignant megakaryocytopoiesis might inform approaches to improve megakaryocyte and platelet production. Lastly, they consider genomic lesions in platelet-function disorders.
Genetically engineered megakaryocytes or HSCs for gene therapy are considered by Wilcox not only to treat or cure inherited genetic disorders of platelet production but also to engineer platelets as vehicles of drug delivery to specific sites in select diseases. The problems with current experimental therapeutic approaches, such as insertional mutagenesis, immune response, altered platelet function, and decreased platelet production, are discussed and considered.
Thus, the articles in this series provide an excellent, detailed update on the tremendous need for safe sources of high-quality platelets, the challenges with current systems, new models of the fundamental process of megakaryocyte and platelet formation that can potentially be tapped for vast improvements, and promising systems and improvements that are on the horizon. We hope that this review series will lead to a new appreciation of how improved megakaryocyte and platelet production can impact human health and will inspire researchers to test creative new approaches that continue to move this important field forward.