Megakaryocytes: Where Are They Now?
By Eva M. Soriano Jerez and Kirk A. Taylor, Ph.D.
Megakaryocytes (MKs) comprise less than 1% of cells within the bone marrow (BM) but generate more than 1,000,000 platelets per second in healthy individuals. MKs are derived from hematopoietic stem cells and mature as they migrate from the endosteal to vascular niche, where they protrude proplatelet extensions through to the venous sinusoid. Platelets circulate for 7-10 days and play roles in inflammation, angiogenesis, and immune responses in addition to their classical roles in hemostasis and thrombosis.
Studies indicate that activated platelets can be split into at least two populations based on surface marker activation/intracellular calcium signalling. However, it is not yet clear whether platelets are ‘plastic’ or if their fate is determined by their MK precursors. If these decisions are a product of fate, does the ‘type’ of MK that generates platelets and where it ‘grew up,’ influence its physiologic function?
Owing to limitations of microscopy techniques, MK biology investigations primarily use the largest pool of BM from the long bones (e.g. femur) as an MK source. However, technological advances and wider access to 2-photon intravital microscopy (2PIVM) have enabled researchers to branch out to other areas, such as the lung and skull.
Looney and colleagues employed 2PIVM in 2017 to report platelet-producing MKs in the mouse lung. This elegant study demonstrated that MKs are resident within the lung and that local microvascular shear conditions contribute to platelet production. Interestingly, Gladwin et al., human MKs isolated from the ribs of thoracotomy patients have larger cytoplasmic volume than those isolated from the posterior ileac crest. This could explain the assertion by Looney and colleagues that approximately 50% of platelets are produced in the mouse lung.
This study was not without controversy and other groups have investigated the role of lung MKs and reached different conclusions. Stegner and colleagues adopted a light-sheet fluorescence microscopy (LSFM) approach to evaluate spatial regulation of thrombopoiesis within the sternum, femur, and cranium. This approach required perfusion fixation of the mice prior to harvesting the bones of interest for LSFM analysis. The authors reported that of the 230 MKs identified in the lungs/sternum of these mice there were very few (0.87 %) that remained in the vasculature. Of note, MKs were distributed relatively evenly through the bone marrow volume of each site that was investigated.
So, from these studies, we understand that MKs reside in different bones and that they have platelet-producing potential, but, how are these platelet factories influenced by their environment? Pariser and colleagues went one step further by performing comparative phenotypic analyses of lung and bone-marrow-derived MKs. Single cell RNA sequencing revealed that MKs isolated from the lung are more closely related to antigen presenting dendritic cells, suggesting that these cells may have roles in immunity. These phenotypes may be influenced by the local environment with the lung being exposed to allergens whereas the BM of the femur is a sterile environment.
Thrombosis is widely recognized as a complication of SARS-CoV-2 infection and resultant COVID-19 disease. Excessive inflammation and triggering of the cytokine storm within the lung vasculature and tissue provides a perfect storm for immunothrombosis. Little is known about the role of MKs during COVID-19 but autopsy reports provide some clues.
A clinical report of 18 patients, who received mechanical ventilation as part of their COVID-19 treatment, had abnormal coagulation profiles and a four-fold increase in the prevalence of MKs within the lung vasculature. It would be interesting to study whether these MKs are also more closely related to antigen-presenting dendritic cells, which could explain their recruitment.
Finally, autopsy reports from five COVID-19 patients at Johns Hopkins University were shown to have MKs within the cortical capillaries of the brain. It is thought that pervading MKs into the brain vasculature could help to explain COVID-19-associated neurological symptoms, such as brain fog.
This leads us to the question: Where are the megakaryocytes now? The short answer perhaps is that they are “everywhere,” but the more important questions are: What is their function? How do MKs respond to different environments? And what are the implications of this plasticity upon platelet production and thrombotic risk?
After all, French and colleagues have shown us that platelet microparticles are able to home back to the bone marrow, delivering receptors to MKs. It will be interesting to see how this exciting field of research continues to develop and what other tricks MKs have hidden up their sleeves!
Eva M Soriano Jerez holds funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 766118