In the larval state, amphibians are able to regenerate a lost limb. But this ability disappears in adulthood. Scientists have succeeded in regenerating the leg of an adult frog thanks to a cocktail of molecules.
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[EN VIDÉO] Stem cells survive the death of the organism Stem cells, undifferentiated, can form, by dividing and specializing, different types of tissue, which makes them promising for regenerative medicine methods. Researchers at the Institut Pasteur have discovered that they can survive for up to 17 days after the death of the organism. Surprised, biologists think that there are keys to better use them.
A lot of’amphibians are able to regenerate a lost limb before their metamorphosis ; once the animals mature, this ability declines sharply. For scientists, understanding the biological mechanisms behind limb regeneration is the first step before a possible application in human medicine. Amputees following a accident where the diabetics, who are prone to necrosis of the extremities, could then simply see their member grow back. Today, it’s more science fiction than reality, but researchers are actively working on this fascinating subject.
The biology department of Tufts University, near Boston in the United States, hosted for more than a year a hundred adult female xenopus, small frogs frequently studied in developmental biology. Amphibians have tested a unique treatment. A cocktail of five molecules taken in a hydro gel which triggered the near-perfect regeneration of their amputated leg. The details of this experiment have been published in Science Advances.
A lost paw, a found paw
The animals had one of their hind legs amputated under General anaesthesia. In the process, the scientists applied at the level of the scar a hydrogel consisting of protein silk which contains the five regenerative molecules: 1,4-DPCA, brain-derived neurotrophic factor (BDNF), growth hormone, and resolvin D5. These molecules participate in the growth of blood vessels, nerves and tissues respectively. Resolvin D5 is a anti-inflammatory. The hydrogel remains in contact with the wound for 24 hours before being removed under anesthesia. Xenopus are thus observed for 18 months without further intervention.
Gradually, the scientists observed the regeneration of the amputated leg in the animals subjected to the treatment. After only two weeks, the benefits of the treatment are already apparent. From nine months, regeneration accelerates until the end of follow-up at 18 months. In all, 75% of xenopus treated showed a newly formed limb with a structure as complex as the native limb, with the presence of blood vessels, bone tissue and functional nerves. Although atrophied, the regenerated limb seems functional and allows the frogs to partially regain their mobility.
If the cocktail of regenerative molecules appears to be effective in xenopus, nothing is less certain in mammals, let alone in humans. Currently, it is unknown if it is possible to regenerate a human-sized limb with this technique. The first step will already be to test it on laboratory mouse.
Regenerative medicine: a hormone helps regenerate limbs on a frog
Article of Marie-Celine Raypublished on November 8, 2018
A new step has been taken for the regenerative medicine : American researchers have partially regenerated a frog’s leg thanks to a “bioreactor” that delivers progesterone directly at the level of the amputated limb.
Will we ever be able to regrow an arm or a leg? For now, this remains science fiction. In the animal world, some living beings are capable of regeneration : flatworms, planarians, cut in half, reconstruct a new organism; lizards regrow their tails and crabs their claws. In mammals, certain tissues, such as the skin, theepithelium intestinal, regenerate for life, but it is impossible to regrow a limb lost by amputation.
Before testing in humans, researchers study animal models. Here, scientists from thetufts university worked on an amphibian, Xenopus (Xenopus laevis), an African frog often used as a model in biology. In this species, the adult has lost the regenerative capacities that exist in the young. After an amputation, this frog only regenerates cartilage, in the form of a kind of spine.
For this study described in the review Cell Reports, researchers have created a portable bioreactor that releases progesterone locally. Progesterone is a female sex hormone, but it also has regenerative abilities. According to Celia Herrera-Rincon, lead author of the article, progesterone also modulates the immune response to promote the healing and triggers the regrowth of blood vessels and bones. »
A 24-hour treatment triggers regeneration over several months
The device developed by the university consisted of a small box with a hydrogel containing progesterone. Immediately after a hind leg amputation, the bioreactor was sewn onto the injury site to deliver progesterone for 24 hours and then removed. This exposure of only 24 hours had a beneficial and lasting effect on tissue regrowth: the frogs partially regenerated their hind limb, while, without treatment, the frogs only regenerated cartilage spines.
With progesterone, the frogs formed a kind of flat leg, like a paddle or a racket. Admittedly, the leg was not perfect and did not have a foot, but it did not contain only cartilage: it had bone, nerves and blood vessels. Finally, from a functional point of view, the animals with their “flat paw” were more active at the locomotor level than those which had only a cartilaginous spine.
The 24-hour exposure was enough to lead to changes for months in the expression of Genoa. This brief treatment therefore triggered a program of tissue growth and remodeling that fostered a long process of regeneration. The experiment worked on an adult frog, which suggests applications in humans. The idea is to find the molecules to apply to reactivate a process that has already taken place in embryonic life, as explained by one of the authors, Michael Levin, at the New Scientist : “Your body knows how to make a limb – it did during embryonic development. »
What if one day our body could regrow a limb?
Article of Jean-Luc Goudet published on July 2, 2016
Why some vertebrates do they manage to regrow an amputated leg or fin? The question, on which biologists have been working for a long time, remains unresolved, but scientists have just provided part of the answer by discovering the same microRNA in three very different species. However, they also exist in humans where, moreover, they function in a similar way.
For a long time, biologists have been exploring this mysterious ability of certain animals to rebuild a complete limb while so many others, including mammals, can only cobble together a stump. However, some scientists think it possible that this function of regeneration is present in all vertebrates but somehow deactivated.
This is the initial idea of Benjamin King and Viravuth Yin, at the University of Maine (United States), who postulate that the same mechanism genetic must be the source of this ability in different species. They chose three, two Pisces and an amphibian (the zebrafish, the senegal polyptera and theaxolotls), separated by about 420 million years of evolution. Good pick, they explain in an article published in the journal Plos One : they actually found a genetic system, based on ten microRNAs (small RNA involved in gene regulation) and four tRNAs (transfer RNA used to read genes).
This set is identical in the three species and seems to function in the same way. The authors were able to link their activity to genes active in the formation of “ blastemas “, these sets of dedifferentiated cells which appear at the level of a major lesion and which will differentiate again to reform the tissues or the entire limb. Cherry on the cake: sequences of these tRNAs exist in the human species.
Many avenues of research, but still few explanations
As for the other studies, this stroke of projector does not illuminate the whole scene and we are still far from understanding this astonishing power. And even further from reactivating it in humans… Previous research had pointed to other mechanisms. Overall, the idea revolves around the regulation of certain genes, involved in the regeneration or formation of theembryo and in cell reprogramming.
At the same zebrafish (Danio rerio), in 2009, a team had shown that proteins, histones, activated genes in an injured limb to trigger tissue regeneration. On this plane, the axolotl (Ambystoma mexicanum), close to salamanders, living in Mexican lakes and famous for spending its life in the larval state (this is the neoteny), is also renowned for its ability to regenerate.
In 2013, we reported on the work of a team that designated the macrophages, cells of the immune response, as triggers of this phenomenon. A cousin, the red-spotted newt, he managed a small feat: heart cells installed in the blastema formed after an amputation are transformed into leg cells. The temptation is great to try to do the same…
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