Mucus, Mechanics and Disease

This story is adapted from an article that originally appeared on the Swanson School of Engineering website.

Mucus, while unpleasant to think about, plays an important role in health. It’s a protective surface that lines organs in the human respiratory, digestive and reproductive systems—and in frog skin.

Researchers from the University of Pittsburgh recently used cells from an aquatic frog species called Xenopus to learn more about mucus and tissue regeneration in humans. Their results were published in Nature Communications. 

Patients with diseases such as asthma, chronic obstructive pulmonary disease and ulcerative colitis produce too much mucus; other conditions, such as injury or surgery, can result in a dearth of the substance.

Goblet cells are the body’s mucus-secretion factories. Because slime creation, amount and transport is so critical to well-being, researchers have long sought the origins of goblet cells and have been eager to control processes that regenerate them and maintain balanced populations.

The team led by Lance Davidson, William Kepler Whiteford Professor of Bioengineering at Pitt, discovered a case of goblet cell regeneration that is both easily accessible and happens incredibly fast on cells isolated from early developing frog embryos. 

“The Xenopus tadpole, like many frogs, has a respiratory skin that can exchange oxygen and perform tasks similar to a human lung,” said Davidson, who leads the MechMorpho Lab in the Swanson School of Engineering. “Like the human lung, the surface of the Xenopus respiratory skin is a mucociliated epithelium, which is a tissue formed from goblet cells and ciliated cells that also protects against pathogens. Because of these evolutionary similarities, our group uses frog embryonic organoids to examine how tissue mechanics impact cell growth and tissue formation.” 

Studying this species is a rapid and cost-effective way to explore the genetic origins of biomechanics and how mechanical cues are sensed, not just in the frog embryo, but universally. When clinicians study cancer in patients, such changes can take weeks, months or even years, but in a frog embryo, changes happen within hours.

“In this project within five hours, they began to change,” Davidson said. “These cells are known to differentiate into a variety of types, but in this scenario, we discovered that they changed very dramatically into a type of cell that they would not have changed into had they been in the embryo.”

Their results were unexpected—so much so that they performed the experiment multiple times to confirm the findings. 

“To our surprise, we found that if we made the environment stiffer, the aggregates changed into these epithelial cells,” explained Davidson. “If we made it softer, we were able to block them from changing. This finding shows that mechanics alone can cause important changes in the cells, and that is a remarkable thing.”

Davidson’s group is interested in how cells, influenced by mechanics, may affect disease states. The results detailed in this article may drive new questions in cancer biology, prompting researchers to consider whether certain kinds of invasive cancer cells might revert to a resting cell type based on their surroundings. 

“When applying these results to cancer biology, one might ask, ‘If tumors are surrounded by soft tissues, would they become dormant and basically non-invasive?’ Or, ‘If you have them in stiff tissues, would they invade and become deadly?’” said Davidson. “These are major questions in the field that biomechanics may be able to help answer. Many researchers focus solely on the chemical pathways, but we are also finding mechanical influencers of disease.”

Hye Young Kim, a young scientist fellow at the Institute for Basic Science and former member of the MechMorpho Lab, will continue this work at the Center for Vascular Research located at the Korea Advanced Institute of Science and Technology. She will study how cell motility changes during regeneration and how epithelial cells assemble a new epithelium, or outer layer. 

Davidson and his lab will explore how this novel case of mechanical cues are sensed by adult stem cells and how these mechanical pathways are integrated with known pathways that control cell fate choices.

“Frog embryos and organoids give us unparalleled access to study these processes, far more access than is possible with human organs,” he said. “The old ideas that regeneration is controlled exclusively by diffusing growth factors and hormones is giving way to the recognition that the physical mechanics of the environment—such as how rubbery or fluid the environment—play just as critical a role."

This research was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health.