A decade ago this summer, at the Marine Biological Laboratory, Jocelyn Malamy watched jellyfish cells "walk" toward each other to close a wound for the first time. An associate professor in Molecular Genetics and Cell Biology at the University of Chicago, Malamy had received transparent, dime-sized medusae of the species Clytia hemisphaerica from Evelyn Houliston's lab at the Marine Observatoire in Villefranche.
The medusa, the free-swimming form most people picture when they hear the term jellyfish, is only one stage of the animal's life cycle. "Clytia are hydrozoans, so mostly they exist as polyp colonies that grow along the surface of rocks or on docks or the underside of underwater leaves," says Malamy. At some point in their life cycle, the colony will start releasing baby medusae. In this way, Clytia's medusae forms are much like flowers, while the polyps are like the shrubs that produce them. We tend to think of the flower—or the jellyfish—as the organism, but these are actually reproductive units. The primary form is the shrub or, in Clytia's case, the polyp colony. Like flowers, medusae are short-lived, surviving only a few months at most. The polyp colonies that produce them, however, can persist indefinitely, much like a perennial shrub that blooms year after year.
Yet unlike other organisms, Clytia medusae can repair damage so rapidly you can actually watch small wounds close within minutes. Larger wounds heal in less than an hour, a rate of recovery humans can only dream of. And unlike in humans, no scar tissue is formed. Instead, Malamy says "healing in the jellyfish looks more like embryonic healing, which is scar-free."
These traits make Clytia a unique window into wound healing. The medusae are transparent, allowing researchers to watch cells move in live animals in real time. Their wounds heal rapidly, and unlike mammals there is no immune system to trigger inflammation around a wound or capillary regeneration to obscure the basic mechanics of repair. As a result, scientists can observe epithelial cells stitching damaged tissue back together. Even more importantly, many of the fundamental mechanisms of wound healing appear to be conserved. "A lot of the processes that we see in Clytia's wound healing are really similar to what you see in all other systems, including mammalian systems," Malamy explains. In fact, she adds "When you're staring at these epithelial cells, you wouldn't know this was a jellyfish. It could be any kind of squamous epithelial cell sheet, and that's nice, because it means that hopefully what we learn in jellyfish can give us insights into other animals as well."
Epithelial cells cover all the body's surfaces. They make up our skin and line the inside of tissues like the gut. Because both the skin and internal epithelial tissues are regularly damaged and must repair themselves, they are a key focus of wound-healing research. Malamy first characterized Clytia epithelial wound healing in 2017 in work initiated with a group of students while she was a Whitman Fellow at the Marine Biological Laboratory (MBL), and she expanded on that work in a paper she co-authored with MBL faculty member Michael Shribak in 2018. Malamy's new paper in the journal Molecular Biology of the Cell uses Clytia to tackle the confusion in the field over the various mechanisms that have been shown to heal epithelial wounds in different organisms, and wounds of different sizes and shapes. She shows that all epithelial wound healing in Clytia is driven by two key cellular structures that act in sequence to close a wound, and defines a mechanism that explains how these structures are coordinated in all types of wounds.
The first structures to form in response to a wound are lamellipodia, which Malamy describes as "foot-like feelers that are actin-rich extensions of the cell." These feelers act as explorers and have an almost fluid-like motion, similar to amoebas. Lamellipodia extend out of cells at the edge of wounds and crawl across the basement membrane, "a protein sheet that's underneath all epithelial cells in all systems," she explains. As they "walk", they drag the cells that produced them forward, eventually stretching the cell body over a wound to close it. Malamy shows in her new paper that these lamellipdodia form even in tiny wounds internal to a single cell, a novel observation.
As the lamellipodia crawl forward, a second wound-healing mechanism comes into play: an actomyosin cable forms at the back of the lamellipodia as they walk forward. As soon as the lamellipodia cover the basement membrane, the cable is triggered to contract.
An actomyosin cable structure is also particularly important if the basement membrane has been damaged. If the "lamellipodia have run into some debris or a tear in the basement membrane, and they can't go any further," Malamy says "the actin cable can pull the cells over the basement membrane damage and also expel wound debris."
As long as there is a basement membrane, lamellipodia will advance, but if the wound is too big, no matter how much the lamellipodia stretch their cells, they won't reach each other. This leads to a collective cell migration being triggered, where the entire sheet of epithelium "lifts itself up and starts walking," Malamy explains. Once the lamellipodia of the cells in the front meet, this large wound can then close the same way as smaller wounds.
"This is a truly elegant mechanism where the system can rapidly adapt to heal all the kinds of wounds that might occur in nature" Malamy says.
Malamy is next planning to examine the mechanisms driving basement membrane repair. "It's great that you can heal a wound by dragging the cells over it," she explains, "but at some point, a damaged basement membrane has to get fixed." She hopes to find out how that happens in Clytia as it's currently unclear how basement membrane repair happens in any system.
You can read the full study here.
