Release of platelets in the lung vasculature. Credit: Image courtesy of University of California – San Francisco
Cells in mouse lungs produce most blood platelets and can replenish blood-making cells in bone marrow, study shows. Using video microscopy in the living mouse lung, UC San Francisco scientists have revealed that the lungs play a previously unrecognized role in blood production. The researchers found that the lungs produced greater than half of the platelets in mouse circulation. In another surprise finding, the scientists also identified a previously unknown pool of blood stem cells capable of restoring blood production when the stem cells of the bone marrow, previously thought to be the principal site of blood production, are depleted.
“This finding definitely suggests a more sophisticated view of the lungs – that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said pulmonologist Mark R. Looney, MD, a professor of medicine and of laboratory medicine at UCSF and the new paper’s senior author. “What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.” The findings could have major implications for understanding human diseases in which patients suffer from low platelet counts, or thrombocytopenia, which afflicts millions of people and increases the risk of dangerous uncontrolled bleeding. The findings also raise questions about how blood stem cells residing in the lungs may affect the recipients of lung transplants.
Mouse lungs produce more than 10 million platelets per hour, live imaging studies show. The new study was made possible by a refinement of a technique known as two-photon intravital imaging. This imaging approach allowed the researchers to perform the extremely delicate task of visualizing the behavior of individual cells within the tiny blood vessels of a living mouse lung.
Looney and his team were using this technique to examine interactions between the immune system and circulating platelets in the lungs, using a mouse strain engineered so that platelets emit bright green fluorescence, when they noticed a surprisingly large population of platelet-producing cells called megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.
More detailed imaging sessions soon revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature, suggesting that more than half of a mouse’s total platelet production occurs in the lung, not the bone marrow. Video microscopy experiments also revealed a wide variety of previously overlooked megakaryocyte progenitor cells and blood stem cells sitting quietly outside the @lung vasculature – estimated at 1 million per mouse lung.
The discovery of megakaryocytes and blood stem cells in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a clever set of lung transplant studies: First, the team transplanted lungs from normal donor mice into recipient mice with fluorescent megakaryocytes, and found that fluorescent megakaryocytes from the recipient mice soon began turning up in the lung vasculature. This suggested that the platelet-producing megakaryocytes in the lung originate in the bone marrow.
“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Muñoz, PhD. “It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”
In another experiment, the researchers transplanted lungs with fluorescent megakaryocyte progenitor cells into mutant mice with low platelet counts. The transplants produced a large burst of fluorescent platelets that quickly restored normal levels, an effect that persisted over several months of observation – much longer than the lifespan of individual megakaryocytes or platelets. To the researchers, this indicated that resident megakaryocyte progenitor cells in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy new megakaryocyte cells to restore proper platelet production.
Finally, the researchers transplanted healthy lungs in which all cells were fluorescently tagged into mutant mice whose bone marrow lacked normal blood stem cells. Analysis of the bone marrow of recipient mice showed that fluorescent cells originating from the transplanted lungs soon traveled to the damaged bone marrow and contributed to the production not just of platelets, but of a wide variety of blood cells, including immune cells such as neutrophils, B cells and T cells. These experiments suggest that the lungs play host to a wide variety of blood progenitor cells and stem cells capable of restocking damaged bone marrow and restoring production of many components of the blood.
The study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production. The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells. https://www.ucsf.edu/news/2017/03/406111/surprising-new-role-lungs-making-blood
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