Lung Regeneration Closer to Reality after New Discovery

Researchers from Weill Cornell Medical College say they have taken an important step forward in their quest to "turn on" lung regeneration - a discovery that could lead to treatment for millions of people suffering from respiratory disorders.

In the journal Cell, the research team claims that they have discovered the biochemical signals in mice that initiate the regeneration of new lung alveoli: the tiny, numerous sacs within the lung where oxygen exchange occurs. Specifically, they found that regenerative signals originate from the specialized endothelial cells that line the interior of blood vessels in the lung.

Though it has been long known that mice can regenerate and expand the capacity of one lung if the other is missing, this study now pinpoints the molecular triggers that initiate this process, and the researchers believe these findings hold relevance for humans.

According to lead author, Dr. Shahin Rafii, "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.”

For the study, Dr. Bi-Sen Ding, first author of this paper, removed the left lungs of mice and studied the biochemical process of subsequent regeneration of the remaining right lung. Prior research has shown that when the left lung of mice is removed, the right lung regenerates by 80 percent, effectively replacing most of the lost alveoli.

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The researchers found that removal of the left lung triggers receptors on lung endothelial cells that respond to vascular endothelial growth factor and basic fibroblast growth factor. Activating these receptors promotes the creation of another protein known as MMP14. The researchers discovered that MMP14, by releasing epidermal growth factors, sparks the generation of new lung tissue.

The next step for researchers will be to determine in MMP14 and other unrecognized angiocrine factors are responsible for lung regeneration in humans as well as mice. According to Dr. Ding, "We believe the same process goes on in humans, although we have no direct evidence yet.” The study’s authors theorize that patients with COPD have so much damage to their lung endothelial cells that they no longer produce the proper inductive signals, thus impairing lung regeneration.

Co-author of the study, Dr. Zev Rosenwaks theorizes that, “"Perhaps replacement of angiocrine factors, or transplantation of normal lung endothelial cells derived from pluripotent stem cells, could restore lung regeneration. 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."

Trigger Discovered Inside Blood Vessels of the Lung for lung regeneration

Trigger Discovered Inside Blood Vessels of the Lung for lung regeneration



A molecular trigger involved in lung regeneration has been uncovered. Investigators--including Dr. Ronald G. Crystal (Chief of Pulmonary and Critical Care Medicine) and Dr. Shahin Rafii (Professor of Medicine/Medicine & Genetics)-- have published their findings in Cell. The discovery is part of a labyrinth of advances toward a fuller understanding of the process of lung regeneration.

Lead investigator, Dr. Rafii (Arthur B. Belfer Professor of Genetic Medicine & Co-Director of WCMC’s Ansary Stem Cell Institute), explains that the pathways involved in the regeneration of liver and of bone marrow can be monitored readily, but it is “much more cumbersome” to study the process in adult organs such as the lung or heart. Using a mouse model, the investigators uncovered growth factor signals that trigger – or “turn on”-the generation of new lung alveoli. Lung alveoli are the numerous, tiny sacs within the lung where oxygen exchange takes place during inhalation and exhalation. The regeneration process the researchers have defined in the journal Cell involves specialized cells (known as endothelial cells), which line the interior of blood vessels in the lung: These endothelial cells--by producing specific growth factors know as angiocrine factors--trigger and sustain the generation of new lung alveoli.

It has been long-known that when a mouse is missing one of its lungs, the remaining lung has the capacity to expand and regenerate. It is speculated that humans may have the same potential, unless, or until, prevented by smoking, cancer, or other extensive chronic damage. Dr. Crystal, co-author of the study, notes there is no effective therapy for patients with COPD. “Based on this study,” he says, “I envision a day when patients with COPD and other chronic lung disease may benefit from treatment with factors derived from lung blood vessels that induce lung regeneration.”


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trigger generation of new lung alveoli

 trigger generation of new lung alveoli



In the Oct. 28 issue of 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.