Taking a Closer Look at our Lungs:
The Discovery of Two Capillary Cell Types
By Adrienne Mueller, PhD
November 11, 2020
"Alveoli, and the surrounding capillaries, were first described by Malpighi more than 350 years ago. The kind of heterogeneity we discovered, where two capillary cell types with distinct functions are part of the same vessel, was unexpected. It had not been described for any organ," shared Ross Metzger, PhD regarding the surprising findings that he recently helped bring to light. The alveoli he describes are small chambers in our lungs that have extremely thin walls, densely packed with a net of capillaries. Capillaries bring blood to the lungs so oxygen from our indrawn breath can be exchanged with carbon dioxide that has built up in our blood. The incredibly thin alveolar walls are comprised of two layers: an outer epithelial layer, separating air from the capillary vessels, and an inner endothelial layer, forming the blood vessel walls. A team of primarily Stanford investigators, led by first author Astrid Gillich, PhD and co-senior authors Dr. Metzger and Mark Krasnow, MD, PhD, recently released a paper in Nature in which they systematically investigated the under-studied capillary vessels and identified two new, molecularly distinct populations of cells that serve different roles in our lungs.
Gas Exchangers and Progenitors
The first cell type that Gillich et al describe is a huge, complex cell with pores that give them a swiss cheese-like appearance. This cell type, which is molecularly unlike any other cell in the body, is so large that it often spans multiple alveoli. Moreover, these cells are also closely associated with cells in the alveolar epithelial layer, the layer close to the air, reflecting a specialized role in gas exchange and leading the authors to dub these cells "aerocytes."
The second cell type that the investigators discovered are much smaller, have few pores, and are about four times more numerous than aerocytes. Because this second cell type resembles capillary cells in other organs, the authors named them "general capillary" cells. By closely studying both cell types over time, the investigators discovered that general capillary cells act as progenitor cells, both for aerocytes and for more general capillary cells, and replenish alveolar capillaries during lung repair and throughout life. Pointing out the surprising differences between these two cell types, Dr. Metzger adds "Nothing about the appearance of the alveolar capillaries had led us to think that they would be made up of two cell types, or that the cells would have such remarkable shapes, unlike those of other capillary cells we’ve seen."
Lungs of the Past and Future
Although the majority of the experiments for this study were carried out in mice, the investigators also confirmed the existence of both of these two novel and distinct cell types in human lung tissue—indicating that both cell types have been conserved in mammalian evolution. When the investigators examined the lungs of reptiles, however, they did not find two distinct cell types - the markers for the two cell types were overlapping. "We found the two capillary cell types in both mouse and human lungs, and they may be unique to mammals. We looked at lungs from alligators and turtles, but they have only a single, unspecialized capillary cell type," summarized Dr. Metzger.
"This discovery transforms our understanding and the textbook description of the alveolus and gas exchange," said Dr. Gillich. With regards to how their findings will influence future research, Dr. Gillich emphasized, "Knowing that there are two cell types changes how we look at lung diseases." Studies to understand and treat many lung disorders, including pulmonary emphysema, acute respiratory distress syndrome, and COVID-19, will benefit from taking the discovery of these new cell types into account. Regarding the significance of this work in our current pandemic, Dr. Gillich adds, "Our findings are especially timely because the alveolus is the site of virus-induced lung injury, including SARS-CoV-2. Capillary cells play important roles in COVID-19, in which fluid leaks from the capillaries into the alveolar space impair gas exchange and can lead to respiratory failure." Additional studies are sorely needed to further determine the role these cells play in healthy lung function and in disease.
Stanford Cardiovascular Institute-affiliated authors who contributed to this work include Astrid Gillich, Fan Zhang, Kyle J. Travaglini, Serena Y. Tan, Mingxia Gu, Jeffrey A. Feinstein, Mark A. Krasnow & Ross J. Metzger.