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. As reported online March 22, 2017 in Nature,
the researchers 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 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
Mouse lungs produce more than 10 million platelets per hour, live imaging
The new study was made possible by a refinement of a technique known as
two-photon intravital imaging recently developed by Looney and co-author
Matthew F. Krummel, PhD, a UCSF professor of pathology. 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.
"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 Emma
Lefrançais, PhD, a postdoctoral researcher in Looney's lab and co-first
author on the new paper.
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
Newly discovered blood stem cells in the lung can restore damaged bone
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,
also a postdoctoral researcher in the Looney lab and the paper's other
co-first author. "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.
"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," said
Looney, who is also an attending physician on UCSF's pulmonary consult
service and intensive care units.
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, Looney said. 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 the new 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."
The observation that blood stem cells and progenitors seem to travel back
and forth freely between the lung and bone marrow lends support to a growing
sense among researchers that stem cells may be much more active than
previously appreciated, Looney said. "We're seeing more and more that the
stem cells that produce the blood don't just live in one place but travel
around through the blood stream. Perhaps 'studying abroad' in different
organs is a normal part of stem cell education."