Surprising new role for lungs: Making blood
Cells in mouse lungs produce most blood platelets and can replenish blood-making cells in bone marrow, study shows
Date: March 22, 2017
Source: University of California - San Francisco
Summary: Using video microscopy in the living mouse lung, scientists
have revealed that the lungs play a previously unrecognized
role in blood production.
FULL STORY
Release of platelets in the lung vasculature.
Credit: Image courtesy of University of California - San Francisco
Release of platelets
in the lung vasculature.
Credit: Image courtesy
of University of California - San Francisco
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 inNature, 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 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
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 mouse lung.
Newly discovered blood
stem cells in the lung can restore damaged bone marrow
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."
Story Source:
Materials provided
by University of
California - San Francisco. Original written by Nicholas Weiler. Note:
Content may be edited for style and length.
Journal Reference:
1. Emma Lefrançais, Guadalupe Ortiz-Muñoz, Axelle
Caudrillier, Beñat Mallavia, Fengchun Liu,
David M.Sayah, Emily E. Thornton,
Mark B. Headley, Tovo David, Shaun R. Coughlin, Matthew F. Krummel,Andrew D.
Leavitt, Emmanuelle Passegué, Mark R. Looney. The lung is a site of
platelet biogenesis and a reservoir for haematopoietic progenitors. Nature,
2017; DOI: 10.1038/nature21706
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