Lab mouse
The lungs may play a previously unrecognized role in blood production, according to preclinical research published in Nature.
Researchers discovered large numbers of megakaryocytes in the lungs of mice and found these cells produced roughly half of the animals’ platelets.
The team also identified a pool of hematopoietic progenitors in the extravascular spaces of mouse lungs that were capable of multi-lineage bone marrow reconstitution.
“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 study author Mark R. Looney, MD, of the University of California - San Francisco.
“What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”
The researchers believe these findings could have major implications for understanding diseases in which patients suffer from thrombocytopenia.
Imaging reveals surprise
This research was made possible by a refinement of a technique known as 2-photon intravital imaging. This approach allowed the researchers to visualize the behavior of individual cells within the blood vessels of a living mouse lung.
Dr Looney and his colleagues used the technique to examine interactions between the immune system and circulating platelets in the lungs in a mouse strain engineered so that platelets emit bright green fluorescence (GFP+).
In this way, the team noticed a large population of 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.
“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 study author Emma Lefrançais, PhD, a postdoctoral researcher in Dr Looney’s lab.
More detailed imaging sessions revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature. This suggests that roughly half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed.
Subsequent experiments also revealed a variety of previously overlooked hematopoietic progenitors outside the lung vasculature.
Transplants provide more insight
The discovery of megakaryocytes and hematopoietic progenitors 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 set of lung transplant studies.
The team transplanted lungs from wild-type mice into mice with GFP+ megakaryocytes and vice-versa. The researchers said they observed proplatelet formation from GFP+ megakaryocytes in the lung vasculature of the GFP+ mice but not in the wild-type mice.
This suggests the megakaryocytes releasing platelets in the lung circulation originate from outside the lungs, the researchers said. And subsequent experiments suggested the megakaryocytes 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, a postdoctoral researcher in Dr Looney’s lab.
“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 GFP+ megakaryocyte progenitors into mutant mice with low platelet counts.
The transplants successfully restored platelet levels to normal, an effect that persisted over a few months of observation—much longer than the lifespan of individual megakaryocytes or platelets.
To the researchers, this indicated that resident megakaryocyte progenitors in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy megakaryocytes to restore proper platelet production.
Finally, the researchers tested whether lung hematopoietic progenitors were capable of multi-lineage bone marrow reconstitution.
They found that cells originating from transplanted lungs traveled to damaged bone marrow and contributed to the production of platelets and other blood cells, including neutrophils, B cells, and T cells.
The researchers said these experiments suggest the lungs play host to a variety of hematopoietic progenitors capable of reconstituting damaged bone marrow and restoring the 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,” Dr Looney said.
In particular, 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, Dr Looney noted.
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.
“These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation,” said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of this study for Nature.
“The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation.”
