How do animals regrow their limbs? And why can't humans do it? - Jessica Whited

For some animals, losing a limb is a decidedly permanent affair. But for salamanders, particularly axolotls, amputation is just a temporary affliction. Not only can they grow back entire limbs in as little as six weeks, they can also regenerate heart and even brain tissue. So how does this astonishing adaptation work?

Regardless of regeneration, every limbed creature had to grow their arms and legs at some point. And whether that process starts in the womb or the world, it almost always begins with little bumps called limb buds. These buds are full of progenitor cells—a cornucopia of cell types that can differentiate into various tissues, including muscles, cartilage, ligaments, and tendons. Some of these progenitors are stem cells, capable of developing into a range of specialized cells and tissues, while others are merely derived from stem cells. But in either case, the progenitors differentiate and multiply rapidly as the limb bud develops.

Nerves grow into the limb from nearby cell bodies and a network of blood vessels form which fuel the process with oxygen. Eventually, that tiny bud grows into a full infant limb. Most salamanders, including axolotls, develop their limbs in the same way. But unlike other animals, they can also start this process all over again if they need to.

When salamanders lose a limb, surrounding skin cells quickly surge across the wound’s surface. This new layer of skin is called the wound epidermis, and once established, it signals cells in the underlying limb stump to undergo something called dedifferentiation. This process reverts nearby cells from fully developed limb tissues back into earlier, less specialized progenitor cells. At the same time, the peripheral nervous system fires up stem cells throughout the salamander’s body.

This would be impossible for most multicellular organisms, whose stem cells typically lose their regenerative capacity with age. But when salamander stem cells near the injury get the right signal, they reactivate and start multiplying. Researchers don’t know what ratio of stem cells and dedifferentiated progenitor cells regeneration requires. But we do know these cells come together to form the most important part of the process: the blastema.

This structure is almost identical to a limb bud—the primary difference is that it’s made of recycled, repurposed cells, and potentially reserved cells, rather than completely new ones. Beyond that, blastemas and limb buds have the same mission: to make thousands of new cells and organize them into the muscle, bone, skin, and nerve tissue required for a functional limb. As this process unfolds, nerves and blood vessels spanning the injury site transmit nutrition and oxygen.

Over several weeks, the stump will steadily grow a miniature limb with translucent skin. And when the process is complete, not only will the limb match the rest of the salamander, there won't even be a scar. The relationship between scarring and regeneration is just one of this processes’ many mysteries. Scientists are still tracking salamander cells on the molecular level to determine how they revert from a mature stage into a regenerative one.

And research into transplanting blastema cells investigates how other animals might replicate this reconstructive wizardry. We also don’t understand how salamanders’ bodies know what part of the limb has been lost or how much needs to be regrown. One theory is that blastema cells have a form of positional memory, allowing them to determine how much to grow in relation to one another.

And it’s equally important to understand how these limbs know when to stop growing to prevent overdevelopment, like in cancerous tumors. But one of regenerations essential ingredients doesn’t belong solely to salamanders: the blastema. Deer antlers use a similar healing tissue to regenerate each year, even though their skin scars like ours. Spiny mice can also restore skin, hair, and some other appendages scar-free.

And even humans can regenerate the tips of our fingers and toes in a surprisingly similar manner. We still don’t know whether this ability is tied to our shared ancestry with salamanders or fueled by distinct biological mechanisms. But with time and research, who knows what evolutionary knowledge we might grow back.