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In this month’s “Paper Of The Month”, research out of UCSF demonstrates that the lung is the main producer of platelets. So far scientist believed that all blood cells – from pathogen-fighting white blood cells to red blood cells that transport oxygen and platelets, which clot blood during wound-healing – are primarily and exclusively produced in the bone marrow. This long-standing view is now being challenged.
A large population of megakaryocytes in the lung
Originally aiming to analyse the interactions between platelets and immune cells, researchers found a surprisingly large population of platelet progenitors called megakaryocytes. Looking into the behaviour of these cells in more detail, it turned out that the lung produces more than 10 million platelets per hour. A number that accounts for approximately half of all platelets in the mouse circulation, making the lung the primary site of platelet biogenesis. Indeed, comparing megakaryocytes in the lung and bone marrow using gene expression profiling and flow cytometry to look at cell maturity markers, revealed megakaryocytes found in the lung to be less mature than their bone marrow counter parts. This indicates a reservoir of immature progenitor cells that reside in the lung and produce platelets.
The technique used to track megakaryocytes and their differentiation into platelets is key to these findings and one reason why this has not been found earlier. Using a microscopy technique called two-photon intravital imaging; researchers were able to track individual cells within the blood vessels of the lung. All in a living mouse, where the cells move freely in their normal environment. Before this technique researchers could only look at snap shots, analysing fixed tissue samples. It was therefore known that megakaryocytes reside in the lung, but the extend was unclear.
To visualise cells of interest, genetically engineered (transgenic) mice are used. The mice carry a mutation (PF4-Cre × Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo), that makes all megakaryocytes glow green due to the expression of a protein called GFP, while all other cells glow red due to the expression of a protein called tomato. These proteins are harmless for the cells and commonly used in science to visualise certain cell types, by linking fluorescent protein expression to the expression of a cell type specific protein. The video below shows you some of the cool images and videos that can be made with this technique.
What role do these megakaryocytes play?
Transplanting lungs from normal mice into the mice harbouring GFP-labelled megakaryocytes revealed that the cells move from the bone marrow into the lung as GFP-labelled cells were detected in the transplanted lungs. However it remains unclear why the cells home to the lung and why the lung is such a good spot for platelet development. The authors hypothesise, that “ the lungs are an ideal bioreactor for the production of mature platelets from megakaryocytes[…]. Beyond the mechanical forces that promote pro-platelet formation and extension, the lung may contain unique signalling partners for megakaryocytes that promote platelet release.” but haven’t proven any such thing in the published work.
The most striking finding in the paper was a different transplantation experiment. Transplanting lungs harbouring GFP-labelled megakaryocytes into transgenic animals (c-mpl−/−) with low platelet counts resulted in increased megakaryocyte activity and a rise in platelet numbers. This rescue lasted months – long past the life span of individual cells, which is 3-5 days, suggesting that the progenitors found in the lung are activated by the low platelet count in the organ recipients and keep actively producing new cells to counteract the lack of cells produced in the bone marrow. It also implicates that progenitors found in the lung are long lived, and not cells coming in from the bone marrow and quickly losing differentiation-potential in their new environment. The lung itself seems to be a reservoir for functionally intact blood cell progenitors.
Megakaryocytes have company
Not just megakaryocyte progenitors were found in the lung vasculature. Blood stem cells such as HSCs and MMPs were also identified in the mouse lungs – a previously unknown reservoir. And these cells are able to, just like the megakaryocyte progenitors, start the production of immune cells subsets such as T and B cells. Using a mouse model in which all cells are fluorescent and transplanting the lungs of these animals into mice lacking blood stem cells (also c-mpl−/−), fluorescent cells were found to travel into the bone marrow, reconstitute the bone marrow stem cell populations such as long term and short term HSCs and start producing T cell, B cells and neutrophils. This verifies the potential of the blood stem cells in the lung – at least when immune cells are lacking.
Overall these results suggest that the bone marrow might not be the only source or reservoir for blood stem cells. This raises a lot of questions: Which other organs have such a stem cell population? Should we look outside of the bone marrow to treat conditions where blood cell counts are low (lymphopenias, thrombocytopenia)? What effect have these stem cells during transplantation?