Lungs Vital in Generating Blood Clotting Platelet Cells

Millions of people worldwide get affected by a condition called thrombocytopenia, a condition characterized by a deficiency of platelets, which functions in blood clotting. Thrombocytopenia causes substantial morbidity and mortality with prolonged bleeding and other health issues. Platelets are produced from big, mature bone marrow cells called megakaryocytes, and each can break up and release thousands of platelets [1]. It is widely believed that platelet production happens in the bone marrow. However, a recent paper by Lefrancais et. al. [2], found that the lung actually contributes to 50% of total platelet productions, and it holds populations of mature and immature megakaryocytes as well as a population of hematopoietic progenitors (stem cells that can turn into megakaryocytes and other blood cells). This has tremendous implications knowing that the lung plays a big role in production of blood cells and platelets.

In the study, different mouse lines were used to conduct the experiment. The first one is a reporter mouse line where the mice' megakaryocytes and platelets would glow green (from green fluorescence protein expression - which "reports" their cell identity and origin from fluorescence). The second mouse line is the control group, also known as the wild type - normal mice. Finally, the third line is the hematopoietic stem cell (HSC) deficient mouse line, where the mice are incapable of repopulating blood cell populations and also suffer from thrombocytopenia (lack of platelets).

With the reporter mouse line, they were able to image and visualize the number of platelets released into the  mouse lung circulation (Figure 1). They found that the lung is responsible for 50% of total platelet production and is a primary site for platelet generation.

Figure 1. Visualization of megakaryocytes and platelets production in the lung. Green indicates the megakaryocytes originating from the reporter mouse line, and red indicates capillaries. Arrows indicate where megakaryocytes are breaking up and undergoing platelet formation. [2].

Interestingly, apart from finding megakaryocytes within blood vessels in the lungs, the study also found megakaryocytes in the lungs outside of the blood vessels that are smaller than the ones in bone marrow and spleen and are less mature. In fact, 85% of the megakaryocytes are situated outside of the vessels and only 15% are within the vessels. To investigate the function of these resident megakaryocytes, they performed a single-lung transplant of the reporter mouse line into the HSC-deficient mouse line that are thrombocytopenic, and they flushed out the megakaryocytes that are in the blood vessels to make sure only resident cells remain - so they can attribute all observed effects to the resident megakaryocytes outside of the blood vessels. It was found that these HSC-deficient, thrombocytopenic mice were able to fully reconstitute platelet counts, which suggested that the implanted lungs had a population of more stem-like progenitor cells that can turn and mature into megakaryocytes. Finally, it was also shown that the lung transplant was able to reverse the condition of having a deficiency in HSCs in the HSC-deficient mice, as the megakaryocytes from the transplanted lung could actually migrate to the bone marrow to reverse HSC defects and associated deficiencies in a subset of blood progenitor cell population.

The results from this study give direct evidence that the lung plays a big role in platelet generation, and it can improve the approach in treating thrombocytopenia. Lung is an essential site where megakaryocytes produce and release mature platelets. The lung is also a residence site for megakaryocytes and hematopoietic progenitor cells, suggesting that it has untapped potential in the generation of blood cells and platelets.

[1] Patel, S. R., Hartwig, J. H., & Italiano, J. E. (2005). The biogenesis of platelets from megakaryocyte proplatelets. The Journal of clinical investigation, 115(12), 3348-3354.

[2] Lefrançais, E., Ortiz-Muñoz, G., Caudrillier, A., Mallavia, B., Liu, F., Sayah, D. M., ... & Krummel, M. F. (2017). The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature.