Each year, an average of 230,000 Italians suffer the fracture of one or more bones. The severity of the diagnosis can lead to several consequences: from a microfracture, which can be healed with plaster or a brace, to multiple and displaced fractures, to which there is no other solution than amputation.
The rate of bone lesions is increasing year by year due to the demographic aging of the population and the increase in sporting activity. Furthermore, 5-10% of long bone fractures evolve into delayed healing or even a recurrence, especially in older subjects.
For this reason it is important to “take a cue” in the medical field from animals that are able to regenerate their tissues more efficiently, such as axolotls.
A recent study puts the spotlight on axolotl, a urodel amphibian capable of fully reviving amputated limbs.
Axolotl, the Peter Pan of salamanders
Life is an evolutionary process: all animals go through different stages to transform from puppies to adults. Some of them keep the same appearance even in mature age, like us humans and common domestic animals; others, on the other hand, go through a process of metamorphosis, completely transforming both their appearance and their lifestyle.
An example of animals that carry out this transformation is constituted by salamanders. The species belonging to the genus Salamander there are seven and they are all urodel amphibians. These animals have a very characteristic life cycle: being an ovoviviparous species, the larvae are deposited in water, where they grow up to metamorphosis, the process that will lead them to fully terrestrial adult life.
Axolotlwhose scientific name is Ambystoma mexicanumis a “bizarre” salamander, since it reaches sexual maturity at the larval stage and spends its entire life as a larva.
This peculiarity makes it an animal with a great regenerative capacity: it is, in fact, capable of completely reform the amputated limbs and some organs.
Before proceeding in detail with the research, let’s better understand how the regenerative process takes place in general.
How does tissue regeneration take place?
The regeneration process of organs and tissues is very important in the animal field, allowing to repair external damage, which could otherwise be lethal.
The various species can adopt different strategies, but, in general, guidelines followed by all organisms can be identified. Mainly two types of regeneration can be distinguished:
- incomplete: in this process the generated tissue is completely different from the damaged tissue; for example, when the parenchyma of an organ is damaged, the wound is repaired by connective tissue;
- complete: in this case the newly synthesized tissue is identical to the damaged one; this occurs in the liver, which is able to completely regrow from a small portion.
It is obvious that the most effective regeneration is the latter, but it is also the most complicated and the least common in more complex organisms.
Depending on the tissue that must be generated from scratch, various types of cells in our organism can be used, including:
- cells of the tissue itself: in this case they are already differentiated cells, which are able to “regress” in the specialization and consequently generate any type of necessary tissue; an example is constituted by the cardiomyocytes which constitute the heart tissue of the zebrafish;
- tissue-specific stem cellswhich can differ only in the different types of tissue in which they are found;
- pluripotent stem cells, which have the ability to generate any type of tissue within the body. The latter are extensively studied in order to find cures for thousands of different pathologies that affect humans, especially degenerative ones.
Regeneration in axolotl
Axolotlas already mentioned, it is a very particular and characteristic organism: is able to completely regenerate all limbs, gills and effectively repair damage to eyes, heart, kidneys, brain and spinal cord.
We could therefore define this little Mexican salamander as an expert in the regenerative field. Where does his superpower come from?
Each fabric of theAmbystoma mexicanum owns tissue-specific stem cells. Therefore, when a limb is amputated, for example, the stem cells are positioned at the level of the wound, forming a structure, called blastema. Some cellular signals subsequently induce cell division at this site, completely reforming the amputated limb.
Most likely this phenomenon derives from an evolutionary adaptation: this organism, in fact, it can survive a predator attack much more easily.
But what are the biochemical processes that lead to the complete regeneration of a limb, activating an active proliferation preventing it from evolving into a tumor? This is the question that many scientists try to answer. This feature makes axolotl the perfect candidate for in-depth studies on cell regenerationsuch as that of bone healing.
Axolotl vs mouse: the study on bone regeneration
Previous studies have already highlighted how important it is to study the regenerative process for different purposes in the medical field.
The first step in analyzing the mechanisms that regulate regeneration in Axolotl is to to compare it with the representative experimental model of mammals (and, therefore, of man), the mouse.
The mouse is a small terrestrial mammal, it has a genome very similar to the human one, it is very easy to raise and generates a very numerous offspring. These features make it the perfect model for genetic, biomolecular and biochemical studies.
First of all, the experiment involved the comparison of the bone structures of the two analyzed species: in both, during development, the skeleton is cartilaginous. The structure of the femoral epiphysis is also similar in axolotls and mice. Another common aspect is the constitution of the bone marrow: in both it occurs that the central part of the bone contains more fat in old age.
In order to better compare the two organisms, axolotls with femoral bones of similar size to the murine ones were chosen, so that the same plate could be applied to the fracture.
Bone fractures of the axolotl and mouse femurs were later caused. Checks were then carried out after 3 weeks and 3, 6 and 9 months. The comparison was also made between amputation and fracture in axolotl in order to better understand both the regeneration of the limb and the welding of a fracture.
In both models examined, the healing process involves the formation of a cartilage callus in the fracture space which is then gradually ossified. The ossification process resulted much slower in axolotl than in mouse. This could be due to the different conditions in which they live: in fact, being an aquatic animal, the Mexican salamander is subjected to external stimuli, which could compromise the correct settlement of the bone.
On the contrary, the regenerative process following the amputation of the limb is much more effective: healing of the limb amputation in axolotl begins with the de-differentiation of the cells which make up the surrounding tissues, followed by a phase of active proliferation leading to the blastema formation; then follows the callus formation and all the other tissues that make up the limb.
It has also been shown that the great regenerative capacity of axolotl is not due to different biomolecular pathways compared to mammalsas to a different modulation of response to the wound stimulus.
For this reason, given the great similarity between the healing process in mammals and axolotls, the biochemical comparison between the healing of the amputated limb and that of the fractured limb could pave the way for the understanding of the regenerative mechanism and new treatments not only for as regards bone lesions, but more generally for most degenerative diseases.
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