Limb regeneration, from the axolotl to human beings

The regeneration of lost or damaged body parts in animals is known from many centuries ago. In 1740 the naturalist Abraham Trembley observed a small cnidarian that could regenerate its head if it was cut off, so he called it Hydra, in reference to the monster from Greek mythology that could grow back its multiple heads if they were cut off. Afterwards, it was discovered that there were many other species of animals with regenerative abilities. In this entry we’ll talk about these animals.

Regeneration in the animal kingdom

Regeneration of body parts is more widespread between the different groups of invertebrates than it is between the vertebrates. This process can be bidirectional, in which both parts of the animal regenerate their missing parts to form two animals (just like the hydra, planarians, earthworms and starfishes) or unidirectional, in which the animal loses an extremity but it just regenerates, without forming two animals (arthropods, molluscs and vertebrates). In vertebrates, fishes and amphibians are the ones that present the greatest regenerative capacities, although many lizards and some mammals are able to regrow their tails.

ch14f01Image by Matthew McClements about bidirectional regeneration in planarians, hydras and seastars. Extracted from Wolbert's Principles of Development.

Regeneration can be done by two different ways:

  • Regeneration without active cellular proliferation or “morphallaxis”. In this type, the absent body part is regrown through remodelling of pre-existing cells. This is what happens in the Hydra, in which lost body parts are regenerated without the creation of new material. So, if a hydra is cut in half, we’ll obtain two smaller versions of the original hydra.
Video about an experiment in which an Hydra has been cut in different pieces. Video by Apnea.
  • Regeneration with cellular proliferation or “epimorphosis”. In this type, the lost part is regenerated via cellular proliferation, it is “newly created”. In most cases, it happens through the formation of a specialized structure called blastema, a mass of undifferentiated cells which appears during phenomena of cellular regeneration.

Almost all groups of animals with regenerative capacities present regeneration with blastema formation. Yet the origin of the blastemal stem cells varies between groups. While planarians present pluripotent (that can differentiate to any kind of cell type) stem cells all along their bodies, vertebrates have specific cells in each type of tissue (cartilage, muscle, skin…) that only regenerate cells of the tissue they come from.

In land vertebrates, lizards and urodeles are the ones that present the most powerful regenerative abilities. Down below we’ll see how they regenerate and the applications it has in modern human medicine.

Expendable tails

When you are a small animal that is being chased by a cat or any other predator, it probably is better for you to lose your precious tail than to lose your life. Some terrestrial vertebrates have evolved following this philosophy, and they are able to shed off their tails voluntarily through a process called caudal autotomy. This allows them to escape from their predators, which are entertained with the still moving lost tail.

 Video in which we can see how some lizards like this red-tailed vanzosaur (Vanzosaura rubricauda) have brightly coloured tails to attract the attention of predators. Video by Jonnytropics.

Autotomy or self-amputation, is defined as a behaviour in which the animal can shed off one or more body parts. Caudal autotomy is found in many species of reptiles and in two species of spiny mouse of the genus Acomys. In reptiles we can find caudal autotomy in lacertids, geckos, skinks and tuataras.

Acomys.cahirinus.cahirinus.6872Foto of a Cairo spiny mouse (Acomys cahirinus), a mammal which is able to shed and regrow its tail. Photo by Olaf Leillinger.

In reptiles, the fracture of the tail happens in specific areas of the caudal vertebras which are naturally weakened. The autotomy may happen in two different ways: intravertebral autotomy, in which the vertebra at the centre of the tail have transversal fracture planes prepared to break if they are pressed hard enough, and intervertebral autotomy, where the tail breaks between vertebras by muscular constriction.

0001-3765-aabc-201520130298-gf03Tridimensional model of the fracture planes on the tail of a lizard and the regeneration post-autotomy of a cartilaginous tube. Image extracted from Joana D. C. G. de Amorim et al.

Caudal autotomy allows the animal to escape, but it isn’t without cost. Many reptiles use their tails as a reserve of fat and losing this energy store is usually detrimental for the animal. That’s why many lizards, once the threat has disappeared, look for their lost tail and eat it, to at least regain the energy it had as fat. In addition, regenerating a new tail requires a great expenditure of energy.

DSCN9467Photo of a Catalonian wall lizard (Podarcis liolepis) that has shed its tail. Photo by David López Bosch.

The regeneration of the tail in reptiles differs from that of amphibians and fishes in that it happens without the formation of a blastema and instead of an actual regeneration of the caudal vertebras, it forms a cartilaginous tube along it. The new tail is stiffer and shorter than the original one, and it usually regenerates whole some weeks after the amputation. Most lizards can regenerate their tails multiple times, but some species like the slow worm (Anguis fragilis) can only do it once. Sometimes, the original tail isn’t completely broken but the regeneration mechanisms are activated, which can lead to lizards and geckos with more than one tail.

056 (2)Detail of the tail of a common wall gecko (Tarentola mauritanica) which has regenerated the tail without losing its original tail. Photo by Rafael Rodríguez.

Urodeles, the kings of regeneration

Of all tetrapods, amphibians are the ones that present the more astonishing regenerative capacities. During the larval stage of most species, both the tail and the limbs (if they have them) can be regenerated after its loss. The scientific community thinks that this is due to the fact that in amphibians the development of limbs and other organs is delayed until the moment of metamorphosis. Yet, frogs and toads (anurans) only maintain their regenerative powers during their tadpole stage, losing them when reaching adulthood.

Wood_frog_tadpoleWood frog tadpole (Rana sylvatica) which, like all amphibians, delays the development of its legs up to the moment of metamorphosis. Photo by Brian Gratwicke.

Instead, many salamanders and newts (urodeles) conserve their regenerative powers their whole life. Even if many species present caudal autotomy, unlike lizards urodeles are able to completely regenerate, not only their tails, but practically any kind of lost body tissue. Of all known species, the axolotl (Ambystoma mexicanum), a neotenic amphibian which reaches adulthood without undergoing metamorphosis, has served as a model organism for the study of the formation of the blastema that precedes regeneration.

 Video about the axolotl, this curious amphibian which is greatly endangered. Video by Zoomin.TV Animals.

Regeneration as it happens in salamanders has stages genetically similar to the ones that occur during the development of the different body tissues and organs during the embryonic development of the rest of vertebrates. In the axolotl (and in the rest of urodeles) regeneration of a limb after amputation goes through three different stages:

  • Wound healing: During the first hour after the amputation, epidermal cells migrate to the wound. The closing of the wound usually completes two hours later with the same mechanisms as in the rest of vertebrates. Yet, the complete regeneration of the skin is delayed up until the end of the regeneration.
  • Dedifferentiation: This second phase, in which the blastema is formed, starts 24 hours after amputation. This is composed both of cells from the specialized tissues of the amputated zone which lose their characteristics (they obtain the capacity to proliferate and differentiate again) and cells derived from the connective tissue that migrate to the amputation zone. When these cells of different origins accumulate and form the blastema, the cellular proliferation starts.
  • Remodelling: For the third stage to start, the formation of the blastema is required. Once the blastema is formed by different dedifferentiated cells, the formation of the new limb follows the same pattern as any kind of vertebrate follows during embryonic development (it even has de same genes intervening).
A_Stages_of_zebrafish_caudal_fin_regeneration_as_longitudinal_sections.Diagram about the formation of the blastema in a zebrafish (Danio rerio) another model organism. Image from Kyle A. Gurley i Alejandro Sánchez Alvarado.

Recently fossils have been found from many different groups of primitive tetrapods which present signs of regeneration. Proof has also been found of limb regeneration in temnospondyl (Apateon, Micromelerpeton and Sclerocephalus) and lepospondyl (Microbrachis and Hyloplesion) fossils. This wide variety of basal tetrapod genera presenting regeneration and the fact that many fish also present it, has led many scientists to consider if the different groups of primitive tetrapods had the ability to regenerate, and if it was lost in the ancestors of amniotes (reptiles, birds and mammals).

Photo of an axolotl, by LoKiLeCh.

However, it is believed that the genetic information that forms the blastema could still be found in the DNA of amniotes but in a latent state. Of the three stages of the regeneration process, the only one exclusive to urodeles is the dedifferentiation stage, as the healing stage is the same as in the rest of vertebrates and the remodelling stage is like the one during embryogenesis. Currently many studies are being carried out on the way to reactivate the latent genes that promote the formation of the blastema in other vertebrates, such as humans.

Some human organs like the kidneys and the liver already have some degree of regenerative capacities, but thanks to investigation with stem cells in animals like salamanders and lizards currently it is able to regenerate fingers, toes, genitals and parts of the bladder, the heart and the lungs. As we have seen, the different animals able to regenerate amputated limbs hold the secret that could save thousands of people. Remember this the next time you hear that hundreds of species of amphibians and reptiles are endangered because of human beings.



During the writing of this entry the following sources have been consulted:

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