Lungs Play Previously Unknown Role in Blood Production

Using video microscopy in a living mouse lung, a team of researchers at the Universities of California, San Francisco (UCSF) & Los Angeles (UCLA), has revealed that the lungs play a previously unrecognized role in blood production.

Lungs Play Previously Unknown Role in Blood Production

Visualization of resident megakaryocytes in the lungs. Image credit: Emma Lefrançais et al , doi: 10.1038/nature21706.
The team, headed by UCSF Professor Mark R. Looney, found that the lungs produced more than half of the platelets — blood components required for the clotting that stanches bleeding — in the mouse circulation.
In another finding, the team 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,” Prof. Looney said.
“What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”
The study was made possible by a refinement of a technique known as two-photon intravital imaging.
The authors 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.
“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said team member Dr. Emma Lefrançais, from the UCSF Department of Medicine.
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, as researchers had long presumed.
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.

Lungs Play Previously Unknown Role in Blood Production

Proposed schema of lung involvement in platelet biogenesis. The role of the lungs in platelet biogenesis is twofold and occurs in two different compartments: (a) platelet production in the lung vasculature; after being released from the bone marrow or the spleen, proplatelets (a1) and megakaryocytes (a2) are retained in the lung vasculature, the first capillary bed encountered by any cell leaving the bone marrow, where proplatelet formation and extension and final platelet release are observed; (b) mature and immature megakaryocytes along with hematopoietic progenitors are found in the lung interstitium; in thrombocytopenic environments, hematopoietic progenitors from the lung migrate and restore bone marrow hematopoietic deficiencies. Image credit: Emma Lefrançais et al , doi: 10.1038/nature21706.
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, Prof. Looney, Dr. Lefrançais and their colleagues conducted a clever set of lung transplant studies.
First, they 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.
In another experiment, the team 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.
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.
“To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” Prof. Looney said.
The findings were published online March 22, 2017 in the journal Nature .