Scientists Discover the Key to Axolotls' Ability to Regenerate Limbs
The axolotl seems like something out of science fiction. This perpetually youthful-looking Mexican salamander possesses a superpower that defies biology as we know it: the ability to regenerate entire limbs, parts of its heart, and even its spinal cord. But how does an amputated limb know whether to regenerate an entire arm from the shoulder down or just a hand from the wrist? This mystery of 'positional identity' has fascinated scientists for decades.
A team at Northeastern University, led by James Monaghan, has unraveled a key piece of this biological puzzle. In a study published in Nature Communications, the researchers reveal an elegant molecular mechanism that acts like a GPS coordinate system for regenerating cells. Surprisingly, the secret lies not in producing more of a chemical signal, but in how quickly it is destroyed.
Monaghan's lab houses about 500 axolotls cared for by a team ranging from undergraduate students to postdocs. 'Raising axolotls involves managing a complex aquatic system and being patient, as they reach sexual maturity within a year. It's slower than with other model organisms, but also more exciting. In many experiments, the team is exploring completely new terrain,' Monaghan says.
For more than two decades, Monaghan's lab has been studying the axolotl to understand how it regenerates complex organs such as its limbs, spinal cord, heart, and tail. His lab's research focuses on uncovering why nerves are essential to this process and what unique cellular properties allow axolotls to regenerate tissues that other animals cannot. These findings could transform our understanding of bodily regeneration and have important applications in regenerative medicine. James Monaghan at work in the lab. Photograph: Alyssa Stone/Northeastern University
'For years we've known that retinoic acid, a derivative of vitamin A, is a crucial molecule that screams to cells 'build a shoulder!'' explains Monaghan. 'But the puzzle was how the cells in the regenerating limb-stump controlled their levels so precisely to know exactly where they were on the axis from shoulder to hand.'
To unpick this mystery, the team focused on a cluster of stem cells that form at the wound site after a limb is lost in animals like the axolotl that are capable of regeneration. Known as the blastema, it's this base of stem cells that then orchestrates regeneration. The prevailing theory was that differences in retinoic acid production might explain why a shoulder (proximal) amputation leads to an entire limb being regenerated, while a wrist (distal) amputation only regenerates the hand.
'Our big surprise was to discover that the key was not in how much retinoic acid was produced, but in how it was degraded,' says Monaghan. The team discovered that cells in the distal part of the limb, the wrist, are awash in an enzyme called CYP26B1, whose sole function is to destroy retinoic acid. In contrast, cells in the shoulder have hardly any of this enzyme, allowing retinoic acid to accumulate to high levels.
This difference creates a chemical gradient along the limb: lots of retinoic acid in the shoulder, little in the wrist. It is this gradient that informs cells of their exact location.
In humans, this pathway of cellular plasticity is absent or closed. 'Therefore, the great challenge is to understand how to induce this blastemal state in our cells, a key transient structure in regeneration. If achieved, it would be possible for our cells to respond again to positional and regenerative signals, as they do in the axolotl,' explains the researcher. Tricking the Cells Into Over-Regenerating
To confirm their discovery, the researchers conducted an experiment. They amputated axolotl legs at the wrist and administered a drug called talarozole, which inhibits the CYP26B1 enzyme. By 'turning off the brakes,' retinoic acid accumulated to extremely high levels in a place where it normally shouldn't. As a result the wrist cells, 'confused' by the high concentration of retinoic acid, interpreted position as being the shoulder. Instead of regenerating a hand, they proceeded to regenerate a complete, duplicated limb. 'It was the ultimate test,' Monaghan says.
Different limb regenerations of axolotls treated with talarozole. Photograph: Alyssa Stone/Northeastern University
The team went a step further to identify which genes were activated by these high levels of retinoic acid. They discovered a master gene that was specifically activated in shoulder areas: Shox . An abbreviation of 'short stature homeobox gene,' Shox is so called because mutations to it in humans cause short stature. 'We identified Shox as a critical instruction manual in this process,' Monaghan explains. 'It's the gene that tells developing cells to 'build the arm and forearm bones.''
To confirm this, the team used Crispr gene-editing technology to knock out the Shox gene in axolotl embryos. The resulting animals had peculiar limbs: normal-sized hands and fingers, but significantly shorter and underdeveloped arms and forearms. This demonstrated that Shox is essential for shaping proximal, but not distal, structures, revealing that regeneration uses distinct genetic programs for each limb segment.
This study not only solves a long-standing mystery of regenerative biology, but also provides a molecular road map. By understanding how the axolotl reads and executes its genetic instructions for regeneration, scientists can begin to think about how, someday, we might learn to write our own genetic instructions. An axolotl. Photograph: Alyssa Stone/Northeastern University
'The axolotl has cellular properties that we want to understand at the deepest level,' says Monaghan. 'While regeneration of a complete human limb is still in the realm of science fiction, each time we discover a piece of this genetic blueprint, such as the role of CYP26B1 and Shox , we move one step closer to understanding how to orchestrate complex tissue repair in humans.'
To bring this science closer to clinical applications, one crucial step is to succeed in inducing blastema formations of stem cells at sites of amputation in humans. 'This is the 'holy grail' of regenerative biology. Understanding the minimal components that make it up—the molecular signals, the cellular environment, the physiological conditions—would allow us to transform a scar into a regenerative tissue,' explains Monaghan.
In his current research, there are still gaps to be filled: how the CYP26B1 gradient is regulated, how retinoic acid connects to the Shox gene, and what downstream factors determine the formation of specific structures, such as the humerus or radius bones. From Healing to Regeneration
Monaghan explains that axolotls do not possess a 'magic gene' for regeneration, but share the same fundamental genes as humans. 'The key difference lies in the accessibility of those genes. While an injury in humans activates genes that induce scarring, in salamanders there is cell de-differentiation : the cells return to an embryonic-like state, where they can respond to signals such as retinoic acid. This ability to return to a 'developmental state' is the basis of their regeneration,' explains the researcher.
So, if humans have the same genes, why can't we regenerate? 'The difference is that the salamander can reaccess that [developmental] program after injury.' Humans cannot—they only access this development pathway during initial growth before birth. 'We've had selective pressure to shut down and heal,' Monaghan says. 'My dream, and the community's dream, is to understand how to make the transition from scar to blastema.' James Monaghan. Photograph: Alyssa Stone/Northeastern University
Monaghan says that, in theory, it would not be necessary to modify human DNA to induce regeneration, but to intervene at the right time and place in the body with regulatory molecules. For example, the molecular pathways that signal a cell to be located in the elbow on the pinky side—and not the thumb—could be reactivated in a regenerative environment using technologies such as Crispr. 'This understanding could be applied in stem cell therapies. Currently, laboratory-grown stem cells do not know 'where they are' when they are transplanted. If they can be programmed with precise positional signals, they could integrate properly into damaged tissues and contribute to structural regeneration, such as forming a complete humerus,' says the researcher.
After years of work, understanding the role of retinoic acid—studied since 1981—is a source of deep satisfaction for Monaghan. The scientist imagines a future where a patch placed on a wound can reactivate developmental programs in human cells, emulating the regenerative mechanism of the salamander. Although not immediate, he believes that cell engineering to induce regeneration is a goal already within the reach of science.
He reflects on how the axolotl has had a second scientific life. 'It was a dominant model a hundred years ago, then fell into disuse for decades, and has now reemerged thanks to modern tools such as gene editing and cell analysis. The team can study any gene and cell during the regenerative process. In addition, the axolotl has become a cultural icon of tenderness and rarity.'
This story originally appeared on WIRED en Español and has been translated from Spanish.
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