Article Date: 31 Oct 2011 – 1:00 PDT
Researchers at Weill Cornell Medical College say they have taken an
important step forward in their quest to “turn on” lung regeneration — an
advance that could effectively treat millions of people suffering from
respiratory disorders.
In the journal Cell, the research team reports that they have uncovered
the biochemical signals in mice that trigger generation of new lung
alveoli, the numerous, tiny, grape-like sacs within the lung where oxygen
exchange takes place. Specifically, the regenerative signals originate
from the specialized endothelial cells that line the interior of blood
vessels in the lung.
While it has long been known that mice can regenerate and expand the
capacity of one lung if the other is missing, this study now identifies
molecular triggers behind this process, and the researchers believe these
findings are relevant to humans.
“Several adult human organs have the potential upon injury to regenerate
to a degree, and while we can readily monitor the pathways involved in the
regeneration of liver and bone marrow, it is much more cumbersome to study
the regeneration of other adult organs, such as the lung and heart,” says
the study’s lead investigator, Dr. Shahin Rafii, who is the Arthur B.
Belfer Professor of Genetic Medicine and co-director of the Ansary Stem
Cell Institute at Weill Cornell Medical College.
“It is speculated, but not proven, that humans have the potential to
regenerate their lung alveoli until they can’t anymore, due to smoking,
cancer or other extensive chronic damage,” says Dr. Rafii, who is also an
investigator at the Howard Hughes Medical Institute. “Our hope is to take
these findings into the clinic and see if we can induce lung regeneration
in patients who need it, such as those with chronic obstructive pulmonary
disease (COPD).”
“There is no effective therapy for patients diagnosed with COPD. Based on
this study, I envision a day when patients with COPD and other chronic
lung diseases may benefit from treatment with factors derived from lung
blood vessels that induce lung regeneration,” states Dr. Ronald G.
Crystal, who is a co-author of this study and professor of pulmonary and
genetic medicine at Weill Cornell.
Dr. Rafii and his researchers had previously uncovered growth factors that
control regeneration in the liver and bone marrow, and in both cases, they
found that endothelial cells produce the key inductive growth factors,
which they defined as “angiocrine factors.” In the current lung study,
they discovered the same phenomenon — that blood vessel cells in the
lungs jump-start regeneration of alveoli. “Blood vessels are not just the
inert plumbing that carries blood. They actively instruct organ
regeneration,” says Dr. Rafii. “This is a critical finding. Each organ
uses different growth factors within its local vascular system to promote
regeneration.”
To conduct this study, Dr. Bi-Sen Ding, a postdoctoral fellow in Dr.
Rafii’s lab and the first author of this paper, removed the left lungs of
mice and studied the biochemical process of subsequent regeneration of the
remaining right lung. Previous pioneering work by Dr. Crystal had shown
that when the left lung of mice is removed, the right lung regenerates by
80 percent, effectively replacing most of the lost alveoli. “This
regeneration process also restores the physiological respiratory function
of the lungs, which is mediated by amplification of various epithelial
progenitor cells and regeneration of the alveolar sacs,” says Dr. Ding.
“This regenerative phenomenon, however, only occurs after a trauma that
abruptly reduces lung mass. Then the specific subsets of blood vessels in
the remaining lung receive a message to start to repopulate alveoli, and
our job was to find that signal,” says Dr. Daniel Nolan, a senior
scientist in this project who developed methods to characterize the lung
blood vessel cells.
The scientists found that removal of the left lung activates receptors on
lung endothelial cells that respond to vascular endothelial growth factor
(VEGF) and basic fibroblast growth factor (FGF-2). Activation of these
receptors promotes the rise of another protein, matrix
metalloproteinase-14 (MMP14). The researchers discovered that MMP14, by
releasing epidermal growth factors (EGF), initiates the generation of new
lung tissue.
When the investigators disabled receptors of VEGF and FGF-2 specifically
in the endothelial cells of the mice, the right lung would not regenerate.
The defect in the lung regeneration was found to be due to the lack of
MMP14 generation from the blood vessels. Remarkably, when these mice
received an endothelial cell transplant from a normal mouse, the
production of MMP14 was restored, triggering the regeneration of
functional alveoli.
“The recovery of lung function and lung mechanics by transplantation of
endothelial cells that stimulate MMP14 production may be valuable for
designing novel therapies for respiratory disorders,” says Dr. Stefan
Worgall, who helped with the functional lung studies in this project.
“This study will also help us understand mechanisms for repair in the
growing lungs of infants and children,” he adds. Dr. Worgall is associate
professor of pediatrics and genetic medicine and distinguished associate
professor of pediatric pulmonology.
Given MMP14′s role, Dr. Rafii classifies it as a crucial “angiocrine”
signal — a lung endothelial specific growth factor responsible for
alveolar regeneration. Dr. Rafii’s team also seeks to reveal the
initiation signals resulting in the activation of lung blood vessels.
“Changes in local blood flow and biomechanical forces in the remaining
lung after removal of the left lung could certainly be one of the
initiation cues that induce endothelial activation,” says Dr. Sina
Rabbany, who is a co-senior author of this study and a professor of
bioengineering at Hofstra University and adjunct associate professor of
genetic medicine and bioengineering in medicine at Weill Cornell.
The researchers will next determine if MMP14 and other as-yet unrecognized
angiocrine factors are responsible for lung regeneration in humans as well
as mice. “We believe the same process goes on in humans, although we have
no direct evidence yet,” says Dr. Ding. The study’s authors theorize that
patients with COPD (a disorder most often caused by chronic smoking) have
so much damage to their lung endothelial cells that they no longer produce
the proper inductive signals. “We know
smoking damages lungs, but lungs may continue to regenerate alveoli,” says
Dr. Koji Shido, a co-author of this study. “But at certain point,
significant injury to the endothelial cells could impair their capacity to
support lung regeneration.”
“Perhaps replacement of angiocrine factors, or transplantation of normal
lung endothelial cells derived from pluripotent stem cells, could restore
lung regeneration” speculates Dr. Zev Rosenwaks, who is the director of
the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine
at Weill Cornell, and a co-author of this study. “Currently, we are
generating pluripotent stem cells derived from patients with genetic
pulmonary disorders to identify potential pathways, which may ultimately
enhance our understanding of how lung endothelial cells may improve lung
function in these patients.”
http://www.medicalnewstoday.com/releases/236793.php
