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With frilled gills, a polite smile and shining green skin, the tiny creature gave scientists great clues to solving one of biology’s greatest mysteries: limb regeneration.
The aquatic salamanders, known as the Axolotls, are known for their unusual ability to re-grow limbs that have been lost due to injuries or amputations. Now, in a new study published Tuesday in Nature Communications, researchers reveal more about the complex processes behind the superpower.
“A long-standing question in this field is, for example, what are the clues to communicate to cells at the injury site to grow on the arm alone?
A substance called retinoic acid, commonly found in the treatment of retinol acne, has been found to be the cause of what parts of the body the injured cells of Axolotl regenerate and how they discovered it.
Retinoic acid is also important in human embryo development, telling cells where to grow their heads, heads and feet, Monaghan explained. However, for unknown reasons, most of our cells lose the ability to “listen” to molecular regeneration cues while in the uterus.
And while regrowing the entire human limbs still seems like a distant science fiction thing, Monaghan said studying the signaling function of retinoic acid in these amphibians could help develop new human healing methods and gene therapy.
Axolotls do not shine naturally in the darkness. To observe cues for retinoic acid signaling, Monaghan’s team used genetically modified axolotls that glows fluorescent green wherever the molecule is activating damaged cells.
Initially, the researchers adopted a more “Frankenstein” approach by injecting excess amounts of retinoic acid into the salamander system and observing the effect. At the cleavage site, axolotls grow more than necessary. Replace your hands with your entire arm.
“Throwing a large amount of retinoic acid into the (injury site) will activate all of these different genes that are probably not related to the blueprint you need,” said Katherine McCusker, an associate professor of biology at the University of Massachusetts Boston University, who is not involved in the study but has researched Salaman limb regeneration.
To better understand how Axolotls used natural levels of retinoic acid for limb regeneration, Monaghan and his team changed their approach.
“We discovered that a single enzyme is responsible for breaking down retinoic acid in the body,” Monaghan said. The same Frankenstein effect occurred again when his team blocked the enzyme. “This is really exciting and it blew us away because it shows that the levels of (natural) retinoic acid are controlled by a breakdown.”
In other words, the injured Axolotl’s hands know that an enzyme called CYP26B1 does not grow into the arms as it blocks the regeneration process from further progressing, explained McCusker.
So far, understanding this relationship in Axolotl’s regeneration system is just one of the puzzles, Monaghan said. The next step is to accurately identify the genes that retinoic acid is targeting within the cell during regeneration, further revealing the “blueprint” that follows these cells.
When Axolotl’s cells get injured, they go through a process called dedifferentiation, which leaves them with “memory” and return to their embryonic state, Monaghan said. In this embryonic state, cells can focus on the production of new limbs and listen, build and grow retinoic acid signals again.
However, human cells do not dedifferentiate upon injury and are unable to respond to retino acid signals. Instead, our tissues respond to scarring, piles of collagen and damage by calling it a day, Monaghan said.
But what if there was a way for human cells to take these orders and build their limbs again?
“This question is very interesting when it comes to gene therapy because you probably don’t need to add or remove any human genes. You can turn on the right genes at the right time, or turn off the right genes at the right time.”
Although human limb regeneration is likely to be far apart in the future, McCusker said that if scientists understand more about retinoic acid signaling, technology can restore this ability to regenerate human cells, treat wounds and prevent scars.
Part of McCusker’s research focuses on how to speed up the process of limb regeneration. With Axolotls, it may take only a few days to play small hands, but in a fully grown person, the process can take years, says McCusker.
“It’s important to continue studying this basic biology,” McCusker said. “We are finding ultra-new ways to do things that we don’t think are possible with today’s human medicine.”