Researchers at the University of Pennsylvania have isolated and characterized a distinct type of lung stem cell in mice and humans that is essential for repairing lung alveoli damaged by respiratory conditions, such as severe influenza. Reporting on their findings in Nature, the UPenn team suggests that the alveolar epithelial progenitor (AEP) cells could represent a starting point for developing new approaches to lung regeneration. Their paper is entitled “Regeneration of the Lung Alveolus by an Evolutionarily Conserved Epithelial Progenitor.”
“One of the most important places to better understand lung regeneration is in the alveoli, the tiny niches within the lung where oxygen is taken up by the blood and carbon dioxide is exhaled,” states Edward E. Morrisey, Ph.D., professor of cell development and biology. “To better understand these delicate structures, we have been mapping the different types of cells within the alveoli. Understanding cell–cell interactions should help us discover new players and molecular pathways to target for future therapies.” Prof. Morrisey is also scientific director of the Institute for Regenerative Medicine at UPenn.
Body organs need to be able to regenerate the structure and function of their tissues after severe injury, the authors explain. Some organs, such as the intestine, contain resident populations of active stem cells that continually replace the epithelial lining. Other, “more quiescent organs,” such as the lung, contain progenitor cells that are only activated after injury to help regenerate the damaged tissues.
The UPenn researchers have now isolated an AEP lineage within the larger population of alveolar type 2 (AT2s) cells that produce lung surfactant. The newly characterized AEP lineage exhibits a distinct gene expression profile, including a high level of lung developmental genes, and a distinct epigenetic signature.
Both the mouse and human AEP cells identified express a conserved cell-surface marker, TM4SF1, which the team used to isolate human AEP cells. Their analyses indicated the human TM4F1 AEP lineage represented about 29% of the human AT2 population. The mouse and human AEPs could also form 3D organoids, in which they generated multiple epithelial cell types. “In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell-surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D lung organoids,” the authors write. Prof. Morrisey adds, “From our organoid culture system, we were able to show that AEPs are an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.”
The team's studies in mice also showed that while the population of AEP cells remained stable when there was no damage to alveoli, the cells expanded rapidly to regenerate the alveolar epithelium in influenza-damaged lungs. “Our data reveal that AEPs are a major lineage that contributes to functional alveolar epithelial regeneration by producing a large number of both AT2 and AT1 cells after injury,” the authors write. They hope that the discovery of both human and mouse AEPs will open the way to new research on stem cell-based therapies for lung disorders. “Importantly, the conservation and accessibility of both mouse and human AEPs provides an opportunity for mechanistic studies to shed light on human lung progenitor cell biology, and assist in the development of new treatments for acute and chronic lung diseases.”
The UPenn researchers have access to more than 300 lungs through the lung transplant program headed by Edward Cantu, M.D., an associate professor of surgery. They aim to closely examine influenza-damaged lung tissue and other models of lung disease to help identify where and when AEP expansion is triggered in response to acute lung injury or more chronic lung disorders.
“We are very excited at this novel finding,” comments James P. Kiley, Ph.D., director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI), which supported the study. “Basic studies are fundamental stepping stones to advance our understanding of lung regeneration. Furthermore, the NHLBI support of investigators from basic to translational science helps promote collaborations that bring the field closer to regenerative strategies for both acute and chronic lung diseases.”