Regeneration seems more like a trick for earthworms or salamanders than for humans, but mammals really can do it too -- and the secret lies underneath your fingernails, scientists say. New research examining the regenerative power of mice points to possible avenues to explore the regeneration of limbs in the future.

In humans and mice alike, the loss of a fingertip isn’t necessarily forever -- bone, nerves and nail can grow back in a few months. New York University researchers examined the molecular mechanisms behind this ability in mice and reported their results last week in the journal Nature. They found that one of the key elements to successful regeneration was a group of stem cells in a part of the nail bed populated by nerve endings and blood vessels, which ordinarily plays a role in every day nail growth.

On a molecular level, the researchers found that a certain protein signaling chain called the Wnt pathway plays a crucial role in regenerating bone. If the Wnt pathway was blocked, the nails and bones of amputated mice did not grow back. And if the researchers manipulated the Wnt-signaling pathway, they could regenerate mouse fingertips amputated farther back than from where they are usually able to regenerate. Wnt-signal manipulation could be key to therapies for regenerating lost limbs -- of both mice and men -- in the future.

“This is encouraging because the similarities give us hope that we will be able to induce human regeneration in the not-too-distant future,” Tulane University molecular biologist Ken Muneoka told Nature’s Ed Yong.

But there is still much to learn about the science of limb regeneration. Our knowledge of the process is thinner in mammals than it is throughout the rest of the animal kingdom, but it’s reasonable to suspect that what’s good for the amphibian might be good for the mammal.

Earthworms have some impressive regenerative powers, but even their success can vary, depending on where the animal is cut. The more head segments an earthworm loses, the less likely it is able to regrow its head. In the common red wiggler worm, the loss of eight segments or less is probably no big deal, but if the cut removes between 8 and 13 segments, the worm might be able to regrow some of its head, but not its sexual organs (which yes, are in the head -- both ovary and testis).

The exact mechanism of earthworm regeneration is not fully understood, but scientists know that nerves play a key role. If an earthworm suffers amputation, and if a portion of the nerve cord near the cut is removed, regeneration fails. Nerves are also required for amphibian limb regeneration.

The axolotl, an aquatic salamander, also requires certain immune system cells called macrophages to regenerate its limbs. In May, Australian researchers showed that wiping out macrophage cells in axolotls prevented them from regenerating lost limbs and resulted in massive scar-tissue buildup. When the scientists allowed the salamanders to regenerate their store of macrophages and cut off the scarred stump ends of the limbs, they regenerated normally.

A certain cellular memory also comes into play. When salamanders regenerate their limbs, the tissues near the edge of the wound revert to a more immature state called a blastema. The cells in the blastema aren’t all-purpose, though; they only regenerate those tissues from which they are derived. Blastema cells that come from muscle tissues will only grow new muscle, and so on.

Since regeneration is found across the animal kingdom, many scientists think that regeneration is something inherited from a very early ancestor. Creatures without broad regenerative ability, like humans, probably lost it over time.

“One of the long-term goals of regeneration research is to understand why humans have such limited regenerative potential and what, if anything, can be done to improve it,” Howard Hughes Medical Institute researchers Ryan King and Phillip Newmark wrote in a 2012 piece for the Journal of Cell Biology.  “The knowledge gained from studying cell biological questions in model organisms should help drive such future efforts of regenerative medicine.

SOURCE: Takeo et al. “Wnt activation in nail epithelium couples nail growth to digit regeneration.” Nature published online 12 June 2013.