Systemic responses are triggered when injury occurs in many organisms and may aid healing and regeneration; this has been seen in mice, salamanders, zebrafish, and planarians. In planarians, the researchers found that the ERK signaling pathway, which spreads along its body wall muscle cells at a faster rate than previously thought, is critical for regeneration, implying a coordinated whole-body regeneration decision-making process that also provides insights into the development of cancer: like an unhealed wound.
In some organisms, damage to one part of the body can trigger healing in another part. Recent findings suggest that this systemic reaction is not a side effect: it is a main feature.
Mice with an injury to one leg had stem cells in the other leg "awakening," as if the cells were preparing to heal the injury. Something similar happens with salamanders, which are masters of limb regeneration. Heart damage in zebrafish triggers certain changes in distant organs such as the kidneys and brain.
"In many different organisms, you can see whole-body responses to injury. But whether those responses actually do anything is unclear," said Bo Wang, an assistant professor of bioengineering at Stanford University. "So that's what we're focusing on."
In a new paper published in the journal Cell, Wang and colleagues found that this whole-body coordination is a key part of planarian wound healing and subsequent tissue regeneration. Understanding what turns regeneration on and off, and how it's coordinated, could also inform research into cancer, which is often thought of as a wound that never heals.
Planarians are half-inch-long flatworms with a superpower: They can regenerate in almost any situation. Cut a planarian into four pieces and you'll have four new flatworms in a few days. As in mice, zebrafish, and salamanders, a wound in one part of the planarian body appears to trigger a response in more distant tissues.
Wang wanted to understand how these responses were coordinated. One possible mechanism is the extracellular signal-related kinase (ERK) pathway. Cells use the ERK pathway to communicate with each other and send signals in the form of waves. If tissue is injured, the nearest cell "passes on" that information to neighboring cells, which in turn tell their neighbors. This wave propagates throughout the organism in a kind of game of telephone.
Now there's just one problem: past research has shown that ERK waves move too slowly to be of any use. "If I propagate a signal at 10 microns per hour, it might take several days to travel through one millimeter," Wang said. At this speed, signals are passed too slowly from one area of the worm to another to aid wound healing and regeneration.
Understanding what turns regeneration on and off could lead to advances in medical treatments and interventions, including with cancer-related effects. Image source: Wang Lab/Stanford University School of Engineering
This may not be a problem for humans. Our circulatory system may allow signals to travel quickly throughout our body. But planarians don't have a circulatory system to speed up this process.
So Wang and his colleagues began tracking the propagation of ERK waves from one end of the animal to the other. They found that signals traveled more than 100 times faster than before. Instead of propagating along the extra-long body wall muscle cells, ERK waves propagate along the extra-long body wall muscle cells. These cells act as "highways," speeding signals from one end of the body to the other. Not days, but hours.
The signals were fast enough to help with treatment, but they still didn't know if the entire body was involved.
To find out, Fan Yuhang, a graduate student in Wang's lab, chopped off the planarian's head. Typically, a planarian's head will quickly regrow from the remaining body after decapitation. But Fan blocked the ERK signal from traveling to the back half of the organism to test whether ERK waves were responsible for coordinating long-distance healing responses. When ERK signaling is blocked, the head not only heals more slowly: it doesn't regenerate at all.
Next, Fan wondered if it was possible to "rescue" the regeneration process and tested this by removing the planarian's tail, which would alert the tail tissue to damage. The tail grew back and surprisingly, the head grew back too.
"What's really interesting is that we can adjust the time delay between amputations," Wang said. If you cut off the planarian's tail within a few hours of the initial injury, you can restart the blocked healing process. But if you wait too long, neither will regenerate.
"What this means is that there is a system in the organism that votes to say, 'OK, now we should grow something,' and everyone has to agree," Wang said. Even the most distant cells have voting rights.
Many animals—such as planarians, starfish, and salamanders—exhibit healing and regenerative abilities that far exceed those of humans. Understanding why we lack this ability could lead to advances in medical treatments and interventions, including with cancer-related effects.
"None of us want the tissue to be in a constant state of injury. This could lead to cancer," Wang explains. His research shows that even in these worms, which have amazing regenerative abilities, most of the time, the regeneration is "off" until the entire body agrees it's time to "turn on."
Furthermore, when Wang and his colleagues tracked the ERK waves spreading through the planarians, they noticed hundreds of genes being turned on and off. Although humans and planarians are very distantly related, we share many of the same genes.
"This gives us an entry point into tracking these genes, which allows us to figure out how animals regenerate while controlling the risk of uncontrolled cancer growth."