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.
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."