Axolotl
“But if salamanders regenerate their limbs, even when kept on dry ground, how comes it to pass, that other land animals are not endued with the same power?"
- Lazzaro Spallanzani, 1768
The axolotl (Ambystoma mexicanum) is an aquatic amphibian native to Mexico, best known for its extraordinary regenerative capacity. Among vertebrates, the axolotl is one of the very few species that retains robust regenerative potential throughout adulthood. It can regenerate not only entire limbs but also the spinal cord, tail, heart, eyes, lens, jaw, and even parts of the brain. This makes it one of the most valuable model organisms in the fields of regenerative biology and stem cell research.
Axolotl regeneration is a form of structural regeneration, primarily mediated by a process called epimorphosis. Regeneration begins when epidermal cells quickly migrate to cover the wound. Under the influence of nerve signals, wound epithelium transforms into the apical epithelial cap (AEC), which secretes key growth factors that activate nearby cells and initiate regeneration. Local cells near the injury site, including connective tissue cells and muscle progenitors, undergo dedifferentiation and regain stemness. These cells accumulate beneath the AEC and form a dense, highly proliferative cluster known as the blastema, which serves as the foundation for rebuilding the missing tissue.
During limb regeneration, blastema cells gradually redifferentiate according to spatial cues along the proximodistal axis—from the shoulder to the fingers. This positional information is guided by the Hox gene family; for example, Hoxa9, Hoxa11, and Hoxa13 are expressed in the upper arm, forearm, and hand regions, respectively. These genetic patterns closely resemble those seen during embryonic development. In addition, conserved signaling pathways such as Wnt, FGF, and TGF-β play important roles in regulating cell proliferation, migration, and differentiation during regeneration, ensuring that the new structures match the original anatomy and function.
A distinctive feature of axolotl regeneration is the presence of positional memory. Cells retain molecular information about their original location. For example, tissue from the distal part of a limb (such as the hand) will only regenerate distal structures even when grafted onto a proximal stump. This indicates that cells maintain their spatial identity during regeneration and cannot easily shift their fate—an insight that has important implications for tissue engineering and regenerative medicine.
Beyond limbs, axolotls exhibit impressive regenerative abilities in the central nervous system. When the spinal cord is completely severed, axolotls can regenerate neurons, glial cells, and vasculature, and even recover full motor and sensory function. Importantly, this regeneration occurs without forming fibrotic scar tissue, which is a major barrier to regeneration in mammals. In the eye, juvenile axolotls can regenerate neural retina through the reprogramming of retinal pigment epithelial (RPE) cells or Müller glia. The heart is also capable of regeneration; following injury, axolotls can restore heart muscle and circulation. Certain regions of the brain, such as the forebrain and midbrain, display partial regenerative capacity as well.
Axolotl regeneration is also strongly dependent on nerve signals. Nerves not only initiate the regenerative response but also maintain the blastema by secreting essential trophic factors, including FGFs and neuregulins. Without adequate innervation, regeneration fails to proceed. Additionally, the axolotl immune system appears to adopt a more permissive, regulated response during regeneration, helping to avoid excessive inflammation and fibrosis. This phenomenon has been described as a "regeneration-permissive immune environment" and is considered a key difference from mammals.
The scientific significance of the axolotl extends far beyond biology. As a vertebrate with complex organ systems and genetic regulation similar to humans, it offers a critical bridge between invertebrate regeneration models and clinical relevance. Axolotl research has the potential to inform therapeutic strategies for tissue repair, neural regeneration, and scarless wound healing in humans.
Famous laboratories that study axolotls:
