Axolotl (Ambystoma Mexicanum)
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The Axolotl (Ambystoma Mexicanum) is a tail lively in the water. The animal is an important model organism to research the regeneration of lost limbs. © Tibor Kulcsar, Imba
Researchers have found out why Axolotl members grow back in the right place. Accordingly, an arm grows with a lost arm because every body cell has a kind of genetic postcode. In the event of an injury, the remaining cells fall back on this genetic position memory and inform the renewable cells in their environment using protein signals about the “correct” postcode of the limb. By targeting these genes and proteins, new tissue of all kinds could be bred in the laboratory or in the human body, according to the researchers.
The Axolotl (Ambystoma Mexicanum) domestic in Mexico are known for the fact that they will fully regrow lost body parts and internal organs within a few weeks. This is also necessary, because the approximately 25 centimeters long ambiguity are aggressive cannibals and nibble on their fellow species regularly. But how do the renewable cells know what kind of body and tissue structure they should develop? After all, a hand looks different than a leg and a thumb different from a little finger.
It is known from previous studies that stem cells on the thumb side of an arm release the signal protein FGF8 and stem cells on the armored side of the small finger. Together, these two signals inform surrounding cells that one arm and hand should grow back here. “What we did not know was which mechanisms ensure that FGF8 and SHH would be switched on on both sides of the arm during regeneration,” explains Leo Otsuki from the Institute for Molecular Biotechnology (IMBA) in Vienna.
“Hand2” gene signals position on the finger side
A team around Otsuki has now examined in more detail where cells know their position in the Axolotl body. The researchers searched for the main mechanism in the genetic and body of the Axolotl, which is based on the position information. The researchers found that each body cell has a kind of genetic postcode even without injury, which indicates its current position in the body as on a molecular card. If a part of the body is lost, the neighboring cells send out a signal that passes on their postcode information to renewable cells. These interpret their own future postcode and then train the corresponding tissue structures.
In the cells on the back of the small finger, this postcode consists, for example, from the gene “Hand2”, as Otsuki and his colleagues stated. This gene is constantly active in the healthy body and reminds the cells of their position in the arm. In the event of an injury, however, gene activity increases and ensures the release of the SHH signal. Surrounding cells that this protein reaches then develop into arm cells on the finger side. Further away cells, however, up to which the SHH signal does not penetrate, however, arm cells of the thumb or front grow. As soon as the arm has grown completely, the genetic activity of “Hand2” sinks back to the starting level and no SHH is produced anymore.
According to the Axolotl, an existing position memory is activated after an injury and its molecular signal is reinforced in order to initiate correct tissue formation. This knowledge is a real breakthrough for rainforation research. “We discovered a more flexible regeneration model when we expected,” says Otsuki.
Renewal body parts in humans?
The discovered postcode and signal code can also be used practically. Because, as Otsuki and his colleagues demonstrate, Axolotl cells can be reprogrammed by placing them in the signal area of a foreign postcode. From an arm cell on the front becomes an arm cell on the back when it gets the SHH signal. With this reprogramming technology, entire fabrics and organoids could be breeded in the laboratory with the desired cell identity, the team hopes.
In the future, tissue may also be changed directly in the human body: “The ability to convert remaining cells after an injury and change their function is of crucial importance for applications in regenerative therapies,” says Otsuki. The technology could therefore produce medical innovations, in which human body cells are transformed into cell types with a different postcode if necessary. “The same hand2 and SHH genes are also available in humans. If there is a similar position memory as at Axolotl in human limbs, scientists could one day use it specifically to release new regenerative skills,” says senior author Elly Tanaka from IMBA. “By using the hand2-expression together with other findings from the Axolotl model, we could finally be able to grow limbs in mammals.”
Source: Leo Otsuki (Imba) et al.; Nature, DOI: 10.1038/S41586-025-09036-5
