Frank McKeon, Ph.D., and Wa Xian, Ph.D. from Jackson Laboratory and their colleagues have identified the a certain lung stem cell, and the role it plays in regenerating lungs.
This work, which appeared in the Nov. 12 issue of the journal Nature, provides some much-needed clarification of the nuts and bolts of lung regeneration and provides a way forward for possible therapeutic strategies that harness these lung stem cells.
“The idea that the lung can regenerate has been slow to take hold in the biomedical research community,” McKeon says, “in part because of the steady decline that is seen in patients with severe lung diseases like chronic obstructive pulmonary disease (known as COPD) and pulmonary fibrosis.”
McKeon noted that there is ample evidence of a robust system for lung regeneration. “Some survivors of acute respiratory distress syndrome, or ARDS, for example, are able to recover near-normal lung function following significant destruction of lung tissue.”
This is a capacity that humans share with mice. Mice infected with the H1N1 influenza virus show progressive inflammation in the lung followed by the death and loss of important lung cell types. However, over the course of several weeks, the lungs of these mice recover and show no signs of previous lung injury.
Because of the presence of such robust lung regeneration in mice, these organisms provide a fine model system to study lung regeneration.
McKeon and his colleagues had previously identified a type of adult lung stem cell known as p63+/Krt5+ in the distal airways. When grown in culture, these p63+/Krt5+ lung stem cells neatly formed alveolar-like structures that were similar to those found within the lung. Alveoli are the tiny, specialized air sacs that form at the ends of the smallest airways, where gas exchange occurs in the lung. Following infection with H1N1, these same stem cells migrated to sites of inflammation in the lung and clustered together to form pod-like structures that resemble alveoli, both visually and molecularly.
McKeon and his colleagues reported that when the lung is damaged by H1N1 infraction, p63+/Krt5+ lung stem cells proliferate and contribute to the development of new alveoli near sites of lung inflammation.
To determine if these cells are required for lung regeneration, McKeon and his coworkers developed a novel system that utilizes genetic tools to selectively remove these cells from the mouse lung. Mice that lack p63+/Krt5+ lung stem cells cannot recover normally from H1N1 infection, and instead exhibit scarring of the lung and impaired oxygen exchange. This demonstrates the key role p63+/Krt5+ lung stem cells play in regenerating lung tissue.
To carry this work one step further, McKeon and his team isolated and subsequently transplanted p63+/Krt5+ lung stem cells into a damaged lung. The transplanted p63+/Krt5+ cells readily contribute to the formation of new alveoli, which nicely illustrates the capacity of these cells to regenerate damaged lung tissue.
In the U.S. about 200,000 people have Acute Respiratory Distress Syndrome, a disease with a death rate of 40 percent, and there are 12 million patients with COPD. “These patients have few therapeutic options today,” Xian says. “We hope that our research could lead to new ways to help them.”