According to a report in the Oct. 28 issue of the journal Cell, investigators at Weill Cornell Medical College have made an important discovery in their mission to “turn on” lung regeneration. This finding could effectively treat millions of individuals who suffer with respiratory disorders.

The team has discovered the biochemical signals in mice that activate production of new lung alveoli – tiny, balloon-like sacs within the lung that inflate and deflate with inhalation and exhalation. These signals come from the specialized endothelial cells that line the interior surface of blood vessels in the lung.

Although investigators have long known that mice re able to regenerate and expand the capacity of one lung should the other be missing, they have now found the molecular triggers behind the process, which could also be relevant to humans.

Head researcher, Dr. Shahin Rafii, explained:

“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.”

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. 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).”

Co-author, Dr. Ronald G. Crystal, said:

“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.”

In a previous study, Dr. Rafii and his team discovered growth factors that control liver and bone marrow regeneration. They found that in both cases, the endothelial cells generate important inductive growth factors, which they described as “angiocrine factors.” The same phenomenon (that blood vessel cells in the lungs triggers regeneration of alveoli) was discovered in the current investigation.

Dr. Rafii explained:

“Blood vessels are not just the inert plumbing that carries blood. They actively instruct organ regeneration. This is a critical finding. Each organ uses different growth factors within its local vascular system to promote regeneration.”

In this investigation the left lungs of mice were removed in order for Dr. Bi-Sen Ding to examine the biochemical process of subsequent regeneration of the remaining lung. According to a prior investigation by Dr. Crystal, when the left lungs of mice are removed, the right lungs regenerate by 80%, effectively replacing a majority of the lost alveoli.

Dr. Ding said:

“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.”

Senior scientists, Dr. Daniel Nolan, said:

“This regeneration 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.”

They discovered that when the left lung is removed, it triggers receptors on endothelial cells in the lung that respond to basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF).

When these receptors are activated they promote the increase of another protein, matrix metalloproteinase-14 (MMP14). They found that MMP14 activates the production of new lung tissue by releasing epidermal growth factors (EGF).

When VEGF and FGF-2 receptors were disabled, particularly in the endothelial cells of the mice, no regeneration occurred in the right lung. This was due to not enough MMP14 proteins generating from the blood vessels. However, when they transplanted endothelial cells from a normal mouse in to these mice, they discovered that remarkably, the production of MMP14 was restored, activating the regeneration of functional alveoli.

Team member, Dr. Stefan Worgall, said:

“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. This study will also help us understand mechanisms for repair in the growing lungs of infants and children.”

Dr. Rafii classifies MMP14 as a vital “angiocrine” signal – a specific lung endothelial growth factor responsible for the regeneration of alveolar. In addition, Dr. Rafii and his team are looking to uncover the initiation signals that result in the activation of blood vessels in the lung.

Co-Senior author, Dr. Sina Rabbany, explained:

“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.”

The next step for the investigators is to find out if MMP14 (as well as other as-yet unrecognized angiocrine factors) are responsible for lung regeneration in humans in addition to mice.

Dr. Ding said:

“We believe the same process goes on in humans, although
we have no direct evidence yet.”

The investigators believe that individuals who suffer with COPD (a disorder usually caused by long-term smoking) have extensive damage to the endothelial cells in their lungs that they can not generate the proper inductive signals.

Co-author Dr. Koji Shido, explained:

“We know smoking damages lungs, but lungs may continue to regenerate alveoli, but at certain point, significant injury to the endothelial cells could impair their capacity to support lung regeneration.”

Co-author, Dr. Zev Rosenwaks, speculated:

“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 steam 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.”

Written by: Grace Rattue