Secrets of axolotl healing could teach us how to regrow limbs

Axolotls have charmed the world with their feathery gills and perpetual smiles. However, their true superpower lies in their ability to regrow lost limbs – even hands, arms, and parts of organs – without leaving a single scar.

This rare ability sets axolotls apart from almost all other vertebrates. Scientists have long looked to them as a living model for unlocking the secrets of regeneration.

Secrets of axolotl healing

In a study led by Northeastern University biologist James Monaghan, researchers asked a question that has puzzled scientists for almost two centuries: How does an axolotl know which body part to rebuild and how much of it to replace?

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

Monaghan traced the animal’s “positional memory” to a common signaling molecule called retinoic acid. Inside the axolotl’s arm, retinoic acid forms a gradient – high near the shoulder, low near the fingertips. Fibroblast cells read that gradient like a map and decide what to build.

“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,’” noted Monaghan.

Rewriting the regeneration plan

To test the system, the team boosted retinoic-acid levels in a salamander’s hand. The result was startling: instead of one new hand, the axolotl sprouted a duplicate limb.

Monaghan said the experiment was “pretty Frankensteiny.” Still, it showed that tweaking the signal can rewrite the regeneration plan.

People make retinoic acid too, and our fibroblasts help mend wounds. The problem is that human cells ignore the signals that axolotls obey. They lay down collagen and form scars instead of new tissue.

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

The genetics of axolotl healing

Digging deeper, the researchers linked retinoic-acid signaling to the short homeobox gene (shox).

When they removed shox with CRISPR-Cas9, the salamanders grew stubby arms capped by normal-size hands – the same limb pattern seen in people who carry a SHOX mutation.

“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,” explained Monaghan.

“How do you make a cell move where you want? Changing its positional memory is critical for this.”

Searching for the healing control switch

Monaghan’s lab is now probing the inner workings of fibroblasts to find out exactly how retinoic acid flips genetic switches like shox.

Cracking that code could bring medicine a step closer to scar-free healing – and, one day, the chance to replace more than a fingertip.

For now, the smiling axolotl keeps teaching us that the blueprints for regeneration are already inside our own cells. The challenge is learning how to read them.

What this could mean for medicine

While limb regrowth in humans may still sound like science fiction, scientists see realistic opportunities for smaller steps in the near future.

Advances in regenerative cues and gene targeting could lead to new ways to treat severe injuries, reduce scarring after surgery, or even regrow damaged cartilage.

Rather than trying to grow an entire arm right away, researchers envision using the axolotl’s secrets to guide healing in stages – like rebuilding bone, restoring tissue layers, or regenerating nerves.

Understanding how fibroblasts respond to positional signals may also open new paths for treating birth defects or degenerative diseases.

The full study was published in the journal Nature Communications.

Image Credit: Alyssa Stone/Northeastern University

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