Originally published 2017-04-03.
Do the lungs make blood? In mice, at least part of it. A study from the University of California, San Francisco (UCSF), published in Nature on 22 March 2017, found that mouse lungs produce more than 10 million platelets an hour, accounting for at least half of all the platelets in the animals' circulation. The team also found a previously unknown pool of blood-forming stem and progenitor cells living in lung tissue.
The finding was specific: it concerned platelets, the tiny cell fragments that help blood clot, and it was shown in mice. It did not mean that lungs make all kinds of blood cells, or that the same proportions hold in people. Even so, it challenged a long-standing textbook picture in which bone marrow does nearly all of the work, and it opened new questions for lung medicine and blood disorders.
Platelets, megakaryocytes and the old textbook view
Platelets are small, disc-shaped fragments that rush to a damaged blood vessel, stick to the exposed wall and clump together to form a plug. Together with clotting proteins, they stop bleeding. A healthy adult has roughly 150,000 to 400,000 platelets in every microlitre of blood, and because each platelet lives only about eight to nine days, the body has to make around a hundred billion new ones every day.
Platelets are shed by megakaryocytes, unusually large cells that push long extensions into blood vessels and pinch off thousands of platelets each. The formation of blood cells in general, called haematopoiesis, has long been thought to take place mainly in the bone marrow, where stem cells give rise to red cells, white cells and megakaryocytes.
Scientists had in fact spotted megakaryocytes in the lungs before, and some had proposed for decades that the lungs might be a site of platelet release. What was missing was a way to watch the process happening in a living animal and to measure how much it mattered.
How the UCSF team watched it happen
The research was led by pulmonologist Mark R. Looney, with co-first authors Emma Lefrançais and Guadalupe Ortiz-Muñoz. They used a refined form of two-photon intravital microscopy, developed with UCSF pathologist Matthew Krummel, which allows researchers to film cells inside the tissue of a living, breathing animal.
The mice were genetically engineered so that their megakaryocytes and platelets carried a green fluorescent protein, originally found in jellyfish. Under the microscope, the cells glowed, so the team could follow them in real time.
Looney's group had been studying how platelets behave during lung inflammation. While imaging the lung blood vessels, they noticed a surprisingly large population of megakaryocytes that seemed to be releasing platelets right there, in the lung circulation. They decided to follow it up properly.
The video below shows megakaryocytes in a mouse lung releasing platelets into the bloodstream.
What the experiments showed
The team reported several linked findings:
- Volume: megakaryocytes in the lung vessels released more than 10 million platelets per hour, about half or more of the animals' total platelet production.
- Origin: when normal donor lungs were transplanted into mice with fluorescent megakaryocytes, glowing megakaryocytes soon appeared in the new lungs. This suggests the cells are born in the bone marrow and then travel to the lungs to release platelets.
- A hidden reserve: about one million blood stem and progenitor cells, including cells that can become megakaryocytes or red blood cells, were found sitting outside the blood vessels in each mouse lung.
- Repair of low platelet counts: lungs carrying fluorescent progenitor cells were transplanted into mice with very low platelet counts (thrombocytopenia). They produced a burst of platelets that brought counts back to normal, and the effect lasted for several months.
- Rescue of bone marrow: in mice engineered to lack blood stem cells in the bone marrow, cells from transplanted lungs moved into the marrow and helped make not only platelets but also immune cells, including neutrophils, B cells and T cells.
Looney said the work points to a more sophisticated view of the lungs
, in which they are a partner in blood formation as well as an organ for breathing. Ortiz-Muñoz suggested the lung might be an ideal "bioreactor" for platelet production, perhaps because of the mechanical force of blood flowing through it or because of molecular signals that are not yet understood.
Why it matters for medicine
Low platelet counts affect millions of people, from patients having chemotherapy to people with immune thrombocytopenia or bone marrow failure, and they raise the risk of dangerous bleeding. Treatments often rely on donated platelets, which can be stored for only about five days at room temperature, so supplies are always under pressure.
The UCSF findings suggest a few new directions:
- Teams trying to grow platelets in the lab from engineered megakaryocytes might learn from the lung environment, or even use it as a model.
- Doctors may need to consider the lungs when patients have unexplained platelet problems, including people with lung disease.
- Lung transplant recipients receive a donor's resident blood stem cells along with the organ, which could affect their immune system in ways that deserve study.
Traci Mondoro of the US National Heart, Lung, and Blood Institute, which helped fund the work, said the team had disrupted some traditional ideas
about the lung's role in making platelets, opening the way for further research.
What it does not mean
"Lungs make blood." That shorthand went viral, but the main finding concerned platelets, not red blood cells or plasma. The lung stem cells could contribute to other blood cells when the marrow was depleted, but in healthy mice the lung's big contribution was platelet release.
"Bone marrow was wrong all along." The marrow is still the main source of blood stem cells and the birthplace of the megakaryocytes that later travel to the lungs. The new picture is one of teamwork between the two organs.
"This is proven in humans." The experiments were done in mice. Megakaryocytes have long been seen in human lungs, and later research has studied them in more detail, but exactly how much human platelet production happens in the lungs is still being worked out. If you have concerns about your platelet count or unusual bruising or bleeding, talk to a doctor.
The bigger lesson
The study is a good example of how new tools change old certainties. The idea that lungs might release platelets was not new, but it took imaging precise enough to watch single cells in a living lung to show how large the role was. It is also a reminder that organs often do more than one job: the lungs, it turns out, filter the blood, defend against infection and, in mice at least, act as a major platelet factory.
Sources: UCSF News, 22 March 2017: Surprising new role for lungs, making blood; Lefrançais E. et al., "The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors", Nature, 2017; Wikipedia: Platelet; Wikipedia: Megakaryocyte.
COMMENTS