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Axolotls, with their signature smiles and pink gills, are the celebrities of the salamander world. But they are more than just cute: They might also hold the secret to regenerating human limbs.

Among biologists, axolotls are famous for their remarkable regenerative abilities that allow them to regrow entire limbs and even organs. Now, James Monaghan, biology chair and professor at Northeastern University, has begun to uncover the secret behind the axolotl's superpower and how it could be used to advance human regenerative medicine.

"It could help with scar-free wound healing but also something even more ambitious, like growing back an entire finger," Monaghan says. "It's not out of the realm [of possibility] to think that something larger could grow back like a hand."

In a paper recently in Nature Communications, Monaghan set out to answer a question that "has plagued the field for 200 years." How does an axolotl know what body part to grow back? If it loses a hand, how does it know to just grow back a hand as opposed to an entire arm?

Monaghan traces this ability, positional memory, back to a molecule known as retinoic acid, which is responsible for telling an axolotl's cells what body part to grow back. Importantly, retinoic acid is not an axolotl-specific molecule—humans also have it, although we mostly get it from our diet and in skin medication like retinol.

By examining axolotls, Monaghan discovered the animals have a gradient of retinoic acid signaling. In the arm, for example, this means axolotls have more retinoic acid in their shoulders—and less of the enzyme CYP26B1 that breaks down the molecule—and less retinoic acid in their hands. The retinoic acid acts as a cue to the regenerative cells, called fibroblasts, telling them what to grow back and how much to grow back.

"The cells can interpret this cue to say, 'I'm at the elbow, and then I'm going to grow back the hand' or 'I'm at the shoulder. I have high levels of retinoic acid, so I'm going to then enable those cells to grow back the entire limb,'" Monaghan says.

Once he understood how key retinoic acid was to the body's signaling, Monaghan started testing the limits of this system in ways that were "pretty Frankensteiny," he says. By adding extra retinoic acid in an axolotl's hand, the salamander grew a duplicated limb instead of just a hand.

Understanding the signal for regeneration is a major step toward applying these lessons to humans, Monaghan says. Humans have retinoic acid and fibroblasts too, but unlike the axolotl's body, where signals are getting sent between all these biological players, the cells in the human body are just not listening in the same way.

When we injure an arm, our fibroblasts lay down collagen and start making a scar. In axolotls, the fibroblasts listen to retinoic acid and "turn back time just a little bit," growing a new skeleton.

"If we can find ways of making our fibroblasts listen to these regenerative cues, then they'll do the rest," Monaghan says. "They know how to make a limb already because, just like the salamander, they made it during development."

However, there is still a lot of work to be done before humans can start regrowing limbs. Monaghan says that understanding the signals in an axolotl's regenerative system is only part of the key. The next step is to understand the mechanics of the cells themselves and what retinoic acid is targeting inside the cells.

Monaghan has already figured out one target: the short homeobox gene, or shox. When retinoic acid signaling increased, shox activated, indicating that the gene is extremely important for regeneration. Removing shox from the axolotl's genome altogether with a gene-editing technique called CRISPR-Cas9, Monaghan found that axolotls would grow very short arms with normal-sized hands.

Notably, this is exactly what happens when humans have a shox mutation, Monaghan adds.

"In order for regenerative biology or regenerative medicine to move forward, we need to understand where positional memory lies and how to manipulate it and engineer it," Monaghan says. "How do you make a cell move where you want? Changing its positional memory is critical for this."

This story is republished courtesy of Northeastern Global News .