The amazing axolotl - legless, but never for long.Wikimedia Commons

Salamanders have the ability to regrow amputated limbs – but what stops a tail growing from the stump, instead of a leg?

A team of scientists are now a step closer the answer. They studied tissue regeneration in axolotls (Ambystoma mexicanum), salamanders endemic to Mexico. The creatures heal so well because the muscle, bone and skin cells nearest to the amputation site revert into a more generic form, forming a clump of adult stem cells called a blastema. These cells then divide and differentiate into the tissue types needed to make a new limb.

One possible explanation was that these undifferentiated blastema cells — which all look identical — are pluripotent and thus able to form many different cells types. But it was not clear how the original cells from adult tissue were reprogrammed, or how the blastema cells went on to form the correct tissue types.

"Everyone, including us, wanted to know how cells from the adult tissues are reprogrammed to make these blastema stem cells," says Elly Tanaka, a cell biologist at the University of Technology in Dresden, Germany, and part of the team.

Take one axolotl

The researchers first added a section of DNA to an axolotl so that it expressed green fluorescent proteins throughout its body. Then they transplanted cells from this animal into a normal axolotl, whose leg they amputated.

Only Schwann cells (green) wrap around the nerve fibers in the axolotl's regenerated limb.D.Knapp/E.Tanaka

As the axolotl regrew its limb, the team tracked the fluorescent proteins to see what happened to each cell type. Despite going through a blastema stage and dividing, the muscle cells did not turn into any other types of tissue. The same was true of Schwann cells, which form a protective sheath around nerve cells. However, other tissue types were more flexible, with dermis cells also able to differentiate into cartilage tissue, but not muscle. The results are reported in Nature¹.

The team also grafted cartilage and Schwann cells from the tip of a limb onto the upper arm of an amputated axolotl. They found that the cartilage cells moved to their old location in the newly-formed replacement limb, whereas the Schwann cells were more widely distributed.

Previous research had shown that blastema from different tissues behaves distinctly despite the uniform appearance of the cells, says Jeremy Brockes, a cellular and molecular biologist at University College, London. But those experiments were not able to track the blastema cells in such detail, he adds. They also relied on using cell in cultures, rather than directly grafting them from one animal to another, which may have interfered with the cells' behaviour, Tanaka suggests.

Researchers will need to learn much more about which molecular signals control blastema cells if they want to adapt the salamander's tricks for therapies in humans, says Tanaka. For example, using the fluorescent protein marker, she hopes to track when particular genes are activated during salamander regeneration, and she is optimistic that regenerating mammal limbs "may eventually be possible".

It is important to discover how molecular signals tell a cell that its neighbouring tissue has been cut off, and what triggers the regeneration process, says Brockes. Following cells during regeneration is a start, but "there's an enormous amount to learn", he says.

• References

  1. Kragl, M. et al. Nature 460, 60-65 (2009).