Can lizards teach us how to regrow lost limbs?

If we lose a limb we’re left with a stump – but lizards and salamanders can regrow their lost appendages. Researchers are now closer to understanding how they do it. Kenro Kusumi and his colleagues at Arizona State University revealed the genetic recipe for regrowing a lizard tail in a paper published in PLOS ONE in August. It turns out they use a different technique to salamanders, one that might be easier for humans to copy.

“To get to the destination of regenerating humans, we need to compare the strategies of different organisms,” says James Godwin, who studies salamander regeneration at the Australian Regenerative Medicine Institute in Melbourne. “This work is a great contribution.”

Some of the genes behind salamander regeneration were revealed last year. Kusumi and his colleagues have now done the same for lizards. Like many of that species, the green anole lizard will drop its tail to avoid a predator. Kusumi was eager to take a closer look to see what happens during the 60 days it takes to regenerate the tail. A developmental biologist with a special in interest in spine regeneration, he points out “the tail is just an elongated spine”.

At first a blood clot plugs the wound, just as it does in salamanders and humans. But what happens next is very different in the three species. In a human, epithelial cells (skin-like cells) migrate in from the edges of the wound to form scar tissue under the clot.

In the lizard, 25 days after amputation, instead of forming scar tissue underneath the clot, a long tube of tissue with a cartilage centre had started growing out. Inside the tube, cells called ependymal cells were laying down tracks along which the torn nerve ends of the spinal cord would grow. And on the outside of the cartilage tube, muscle fibres were growing to encase it. The completed structure shows none of the segmentation of the nervous system and muscle that was in the original tail – but it did the job. “It’s more of a biological prosthesis than a perfect replica,” says Kusumi.

But in a salamander the repair is a perfect replica. And not just for tails but also for limbs, heart, spinal cord and parts of the eye and brain. A salamander’s epithelial cells grow on top of the clot rather than underneath. And then something remarkable happens. A signal from immune cells called macrophages inside the clot travels to the shattered tissues underneath, and instructs those tissues to wind back their biological clock. They form an embryo-like mound called a blastema that has all the 3D pattern information it needs to regenerate the missing organ – perfectly. Take a blastema from a salamander’s cut-off leg, and it will reform that leg even if it is transplanted to another part of the body, says Godwin. It takes three to six months to grow back.

The lizard recruits existing reserves of stem cells from its muscles, cartilage and nerve tissue

In the PLOS ONE paper, Kusumi looked for clues to the differences by examining the 326 genes that were active across the regenerating lizard tail.

Just as placards at a building site identify the construction crews, the genes revealed the signatures of crews of cells at work in the tail. Many of these crews were involved in wound healing and muscle growth, similar to what you see in the salamander. But there was a crucial difference. All along its regenerating tail, the lizard carried the genetic placards of a stem cell crew – Wnt and pax-7 genes.

Lizards and salamanders alike
Salamanders like the Mexican Axolotl have the ability to wind the clock back on their tissues but higher up the evolutionary tree, animals from lizards onwards lost that ability. Credit: Stephen Dalton/Minden Pictures/Corbis

The salamander winds back the clock on existing tissues to return them to an embryonic state; it appears the lizard recruits existing reserves of stem cells from its muscles, cartilage and nerve tissue.

Kusumi says this is potentially good news for human regeneration. Salamanders and fish have the ability to wind the clock back on their tissues (a process formally called dedifferentiation) but higher up the evolutionary tree, animals from lizards onwards lost that ability. Yet the lizard can still regenerate an imperfect tail, and nicely sculpt the muscles to go with it.

Humans can’t do this. When we are bitten by a shark, for instance, there’s some muscle regrowth but never any re-sculpting of the muscle. “If we could learn from the lizard how to sculpt stem cells into muscle, that would be a great advance. The tail has given us a template,” Kusumi says.

Godwin agrees, but points out a tail is a limited appendage compared to an arm or leg. “It’s really cool we know this is a stem cell mechanism,” he says. “We have to turn over every rock to look for clues if we want to understand regeneration.”

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