PITTSBURGH (Jan. 31, 2020) … Let’s talk about slime.
Mucus is a protective, slimy secretion produced by goblet
cells and which lines organs of the respiratory, digestive, and reproductive
systems. Slime production is essential to health, and an imbalance can be life-threatening.
Patients with diseases such as asthma, chronic obstructive pulmonary disease
(COPD), and ulcerative colitis produce too much mucus, often after growing too
many goblet cells. Loss of goblet cells can be equally devastating - for
instance during cancer, after infection, or injury. The balance of slime
creation, amount, and transport is critical, so doctors and medical researchers
have long sought the origins of goblet cells and have been eager to control
processes that regenerate them and maintain balanced populations.
Recently, a group of bioengineers at the University of
Pittsburgh discovered a case of goblet cell regeneration that is both easily
accessible and happens incredibly fast on cells isolated from early developing
frog embryos. Their findings were published this week in the journal Nature Communications (DOI: 10.1038/s41467-020-14385-y).
Lance Davidson, William Kepler Whiteford Professor of
Bioengineering at Pitt, leads the MechMorpho
Lab in the Swanson School of
Engineering where his researchers study the role of mechanics in human
cells as well as the Xenopus embryo - an aquatic frog native to South
“The Xenopus tadpole, like many frogs, has a respiratory
skin that can exchange oxygen and perform tasks similar to a human lung,”
explained Davidson. “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 the larva against pathogens.
Because of these evolutionary similarities, our group uses frog embryonic
organoids to examine how tissue mechanics impact cell growth and tissue
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, we took a group of mesenchymal cells out
of the early embryo and formed them into a spherical aggregate, and 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.”
The lab surprisingly uncovered a case of regeneration that
restores a mucociliated epithelium from mesenchymal cells. They performed the
experiment multiple times to confirm the unexpected findings and began to look closely
at what microenvironmental cues could drive cells into an entirely new type.
“We have tools to modulate the mechanical microenvironment
that houses the cells, and 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 the stiffness or softness of 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
Hye Young Kim, a young scientist fellow at Institute for Basic Science (IBS) and former member of the MechMorpho Lab, will continue this work at the Center for Vascular Research located at Korea Advanced Institute of Science and Technology (KAIST). She will study how cell motility changes during
regeneration and how epithelial cells assemble a new epithelium. Davidson and
his lab will explore how this novel case of mechanical cues are sensed by
mesenchymal cells and how these mechanical induction 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 (NHLBI)
of the National Institutes of Health.
Image caption: "Green Slime covers the surface of a
tadpole (bottom) and a goblet-cell regenerated aggregate (top, not the same
scale). The images show the molecule intelectin-1, an important factor in
tadpole skin, and one of the slime factors synthesized and secreted by goblet
cells (single goblet cells can be seen in the aggregate). In human lung,
intelectin-1 binds bacteria and is on the front line of the innate immune
system. Images courtesy of Hye Young Kim and Lance Davidson."
Contact: Leah Russell