Axolotls could help in regeneration!
You might be reading this headline for the first time, but it is true. When it comes to regeneration, Urodele Amphibian, better known as Axolotls (Ambystoma mexicanum) are the champions. They don’t form scars on wounds, instead they regrow their lost parts. Scientists are hopeful for human limb regeneration based on this knowledge.
Like their striking regeneration ability, they possess distinguished larval features as well. These include a flat body, dorsal fins, three pairs of protruding feathery gills, and a slight grin. They can grow up to one foot. These long-living Mexican salamanders live up to 15 years.
Unlike other salamanders that metamorphose into terrestrial amphibians, the fleshy-pink Axolotls defy the biological laws of metamorphosis. They hold onto their juvenile features throughout their adulthood, so they are known as neonates.
When there can be 300 up to thousands of salamanders born, there is tough competition for food and space in the sole habitat of Lake Xochimilco in Southern Mexico. Being permanently aquatic, unfortunately the salamanders don’t seem to cherish many survival options. (You’d better let them feast on their siblings instead of them feasting on your limb!) This cannibalistic nature might be the reason for their regenerative powers.
The Axolotls used to be the top predators of their ecosystem, preying on worms, mollusks, and insect larvae. They are now being preyed upon by storks, herons, and large fish, like common carp (Cyprinus carpio) and tilapia (Oreochromis niloticus).
FAO-United Nations introduced those two large fish to raise the protein table of the region. However, urbanization, drainage projects, and the heavy metal contamination are a leading factor of population retreat in the Xochimilco Lake waters. Because they are a delicacy for the locals, this causes the population to further decline. Axolotls are critically endangered. However, their regenerative abilities have made them favorite lab pets.
Axolotls Striking Features!
The superpower of the Axolotl is its ability to regrow its limbs and most of its vital organs. Urodeles are the champions when it comes to embryonic regeneration. They can perfectly regrow a limb within a few weeks after amputation.
Many animals can regrow their lost parts, including spineless invertebrates i.e., hydra, and vertebrates, like frogs. Tetrapoda can regenerate complex organs as embryos and turn off the responsible genes as they reach adulthood. But Axolotls are supreme because they keep this incredible ability throughout life.
The Axolotls can also regrow various internal vital organs including their heart, lungs, ovaries, retina, spinal cord, and even some parts of their brain. Thus, a prime solution for human organ regeneration is hiding in Axolotls. Limb regeneration is best studied. It was first reported in 1768 by Spallanzani.
Axolotls as Lab Model in Regeneration Research
The Axolotls are now referred to as “Conservation Paradox.” This is because Axolotls are critically endangered in the wild habitat, but abundant in research laboratories. Owing to their regenerative ability, they are now an important lab model for research in genetic engineering for cancer. They provide an excellent information pool on cellular and molecular mechanisms regarding limb regeneration. Also, their reproduction rate is high, making them much more desirable as biological research organisms.
Scientists attribute this fascinating ability to their neoteny; traits from their embryonic stages help in regeneration. They are immune to Cancer (continuous regeneration/over reproduction leads to tumors/cancer). For this reason, they are the favorite laboratory research model. Scientists are working to harness this ability of Axolotl genes for human limb regeneration.
Basic Regeneration Process in Axolotls
In Axolotls, the basic process of regeneration starts with a blood clot immediately sealing the amputation site. Multiple body tissues including dermal tissues, muscle tissues, nerve tissues, and blood vessels, all contribute to the wound site or the progenitor zone, where they homogenize into stem cells and wound epidermis. The stem cells congregate into the ‘magical blob’ called a blastema. This induction is crucial for successful regeneration.
Blastema differentiates into the diverse type of cells relevant to the severed part. To restore the limb to functionality, all the contributing tissues must regrow coordinately. The cells begin tissue development in the same way as in embryonic stages. The blastema divides and grows into the exact size and the orientation as of the predecessor limb within a few days. Even the amputation seal disappears.
How can Axolotls Regrow
To understand how Axolotls can regrow their lost appendage, scientists strive to understand all the changes that occur during regeneration. Various notable scientists have rendered their priceless services in this regard.
Connective tissues are identified as a potential precursor to regeneration. Connective tissues encompass various cells including fibroblasts, peri skeletal cells, skeletal, fascia cells (muscle), and blood vessels (Currie et al., 2016).
Currie et al. used live imaging of brain bow transgenic axolotls to define the roles of each type of connective tissue in Blastema formation and regeneration:
“Two cell types, chondrocytes, and pericytes showed limited contributions to digit regeneration, while dermal fibroblasts and periskeletal cells contributed to varied animal tissue types and thus, the regenerate” (Currie et al., 2016).
Cell migration is the key. The distance covered by the cells depends on the extent of amputation. For a fingertip, the salamander redirects cells within 0.2 mm, but in the case of a wrist or hand, cells are rerouted from half a meter.
Kragl et al. reported that these cells keep positional memory. They say, “connective tissue-derived cells possess positional memory vital to regrow only the missing appendage, and not a whole new limb at the point of amputation” (Kragl et al., 2009).
It is a cell-type-specific property. Not all cells have this memory. Cartilage-derived cells possess this memory, but Schwann-derived cells do not. Muscle cells, however, lack positional memory and instead develop on cues from connective tissues.
Apart from connective tissues, nerves are also important for regrowth. It is suspected that nerves secrete some substances that lead the process. The absence of nerve hinders the regenerative process and a scar is formed instead, however, the substances still await identification (Makanae, Mitogawa, & Satoh, 2014).
How does an Axolotl read the signals that it is an amputated arm and not a wound? It was hidden in the simple interaction between the nerves, BMP (bone morphogenic protein), and FGF (fibroblast growth factor) (Makanae et al., 2014).
How do Axolotls Manage Limb Regeneration?
How the Axolotls manage the rearrangement of cells, regeneration, and orientation of the limbs is of great interest to scientists. To understand how and which particular genes are turned on or off during the regeneration process, scientists had to sequence its genome. The Axolotl genome is ten times the dimensions of the human genome. With its 32 billion base pairs, it is the largest animal genome to date. This makes it difficult to identify, so they must test hundreds of the genes for their limb regeneration functionality.
Flowers and her colleagues suspected and tracked 25 genes in a genetic barcode using CRISPR/Cas9. Of these 25 genes, they identified two genes directly involved in tail regeneration in Axolotls; the catalase gene and the fetub gene.
The findings are important for human beings, as both genes are present in us, however, they differ in functionality. The fetub gene that is involved in regeneration in Axolotl regulates responses to hepatocyte growth factors, inflammation, and insulin in humans.
How Many Times Axolotls Can Regenerate?
Regeneration is the prerequisite of survival for Axolotls. Limb regeneration frequency is however limited in Axolotls. They can potentially regenerate only five times. After the limit exceeds, scar tissue is formed as seen in humans. This signals the scientists to identify the genes that are turned on or off at this moment.
How close is Science to Regenerating Human Limbs?
Mammals are not inept at regeneration. It is just a lost ability. A far cry from Axolotl's ability to develop a fully functional forelimb, humans have shown the regenerative potential for the loss of fingertips, liver tissues, muscles, and skin.
Regeneration in these areas, however, doesn’t efficiently replace the lost tissues. Entire muscle cannot be as efficiently replaced as damaged muscle fiber. Dermis damage followed by injury leads to fibrosis. Likewise, a Bone fracture (with a gap) is not repaired as efficiently as other damages (Roy & Gatien, 2008).
Humans lose their regenerative abilities with age. The decline in regenerative ability can be attributed to the decrease in the responsiveness of stem cells. An anomaly in fibroblasts (that keeps positional memory and plays an important role in the regeneration of Axolotl) has a role in degenerative response in humans.
Some of the crucial ingredients for limb regeneration are missing or turned off in humans. Scientists are optimistic to discover that secret ingredient of Axolotl’s magical regenerative recipe that would promise scar-free wound healing and organ regeneration in humans.
The knowledge of the responsible genes/factor is a pressing need in the 21st century. Positional memory is the most appealing feature of Axolotl’s regeneration that scientists want to harness in the human models. Their resistance to cancer induction is remarkable. Also, the process is age-independent. These features make Axolotls much more desirable as research models. There are chances that regeneration can be reawakened in humans. It would help in organ regeneration, skin burn treatment, stem cell regeneration, and may even fight against cancer. Ultimately, it will help improve the quality of life.
Nida Riaz is a freelance blogger based in Pakistan. She started writing about her passion for the environment when the world came to a stop in early 2020.
Currie, J. D., Kawaguchi, A., Traspas, R. M., Schuez, M., Chara, O., & Tanaka, E. M. (2016). Live Imaging of Axolotl Digit Regeneration Reveals Spatiotemporal Choreography of Diverse Connective Tissue Progenitor Pools. Dev Cell, 39(4), 411-423. doi: 10.1016/j.devcel.2016.10.013
Kragl, M., Knapp, D., Nacu, E., Khattak, S., Maden, M., Epperlein, H. H., & Tanaka, E. M. (2009). Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature, 460(7251), 60-65. doi: 10.1038/nature08152
Makanae, A., Mitogawa, K., & Satoh, A. (2014). Co-operative Bmp- and Fgf-signaling inputs convert skin wound healing to limb formation in urodele amphibians. Dev Biol, 396(1), 57-66. doi: 10.1016/j.ydbio.2014.09.021
Roy, S., & Gatien, S. (2008). Regeneration in axolotls: a model to aim for! Exp Gerontol, 43(11), 968-973. doi: 10.1016/j.exger.2008.09.003