Axolotl Shows Promise in Unlocking Skin Regeneration Secrets

For over 200 years, researchers have been captivated by axolotl salamanders (Ambystoma mexicanum) and their remarkable regenerative abilities, seeking to uncover secrets that could revolutionize regenerative medicine, including the scarless healing of wounds.

“The axolotl salamander is the most studied animal ever in science for its neotenic ability to regenerate,” Jill S. Waibel, MD, dermatologist and researcher in Miami, said in an interview. Neotenic tissue retains a juvenile or immature state throughout an organism’s life. In the case of the axolotl, “it can regenerate limbs, part of its heart, even its brain,” she said.

A 2019 review of several studies on the regenerative abilities of axolotls highlights the importance of gene activity in controlling its skin regeneration. Specifically, growth factors such as fibroblast growth factors, transforming growth factor beta, and Wnt play a key role in guiding how the creature’s skin cells behave during healing and regrowth. The immune response, particularly the actions of macrophages and neutrophils, is also crucial in the early stages of regeneration, as these cells clear away dead tissue and kickstart the healing process.

After studying the axolotl for the past 8 years, including mapping its genetic makeup, Waibel and researchers at RegenX Science are developing a line of cosmeceutical and over-the-counter products containing urodele collagen extract derived from the creature’s neotenic tissue, without harming the animal. In axolotls, Waibel explained, damaged neotenic tissue “still thinks it’s in fetal mode, so if it injures its muscle, bone, nerves, collagen, or skin, everything will redevelop. After a few months in utero, that process stops in humans, but it never stops in the axolotl. The axolotl has scarless healing and immunity because of antimicrobial properties found in the neotenic tissue.”

RegenX scientists have developed a proprietary decellularization process that renders the urodele collagen extract safe and effective for use in humans. “We then harnessed a reservoir of bioactive peptides, which are small proteins that come from the axolotl, but they don’t contain any RNA or DNA that could confer the risk of any diseases or cancer,” she added.

According to Waibel, who is also subsection chief of Dermatology at Baptist Hospital and past medical director of the Miami Cancer Institute’s Multidisciplinary Skin Cancer Clinic, Miami, genetic analysis of the axolotl revealed genes that have not been seen in humans. The urodele collagen extract also has anti-inflammatory and analgesic properties. “It decreases TNF [tumor necrosis factor] and IL-23 and stimulates regenerative pathways like FETUB (Fetuin-B), which is a gene involved in tissue regeneration,” she said. “We’re exploring these for some products.”

Institutional Review Board–approved human clinical trials at three US sites are nearly complete for evaluating an antiaging hydrating daily serum, an antiaging serum for damaged skin, and a restorative serum to be applied following cosmetic procedures, all containing the extract. The product furthest along is a “super gel” that contains properties of the urodele collagen extract.

In a proof-of-concept study using a third-degree burn model in two pigs, Waibel and colleagues at the University of Miami, Coral Gables, Florida, found that 3 days after the injury was induced, application of the gel led to 92% reepithelialization of the pig’s skin, compared with only 54% in untreated skin.

Shortly after this study was conducted, a burn patient was referred to Waibel — 4 years after he was struck by lightning while fishing on a boat in Mississippi, an accident that resulted in the loss of his right arm and both legs. During a telemedicine consultation, Waibel noticed open ulcers on his chest. “What are those from?” she asked. “They’re from my accident 4 years ago,” he replied. After the man flew to Miami for an in-person evaluation, Waibel treated his ulcers with a fractional laser to debride the wound, then applied the gel as part of a proof-of-concept approach, testing its potential in a real-world patient setting. Within 3 weeks, the long-standing ulcerated area had healed completely, marking the first time a human was treated with the super gel, she said.

Looking ahead, the million-dollar question, Waibel noted, is how much healing can be achieved in humans with formulations of axolotl-derived technology. “For example, can we help a spinal cord injury patient? That sounds like a science fiction movie but there are proteins in genes in this animal that we have turned off that potentially can be turned on in a human,” she said. “It’s very exciting.”

Arisa E. Ortiz, MD, director of Laser and Cosmetic Dermatology at the University of California, San Diego, and current president of the American Society for Laser Medicine and Surgery, who was asked to comment on this work, said that the use of urodele collagen extract derived from axolotl tissue “is an exciting innovation, especially given its unique properties like scarless healing and antimicrobial activity.” While the results from preclinical and proof-of-concept studies are promising, “a key limitation lies in understanding the extent to which these findings will translate to human applications,” Ortiz said. “Overall, this research contributes significantly to the fields of regenerative medicine and dermatology, offering hope for more effective treatments in the future,” she added.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to provide her insights on the topic, said that if researchers could replicate the axolotl salamander’s ability to regenerate its own limbs and organs, “medicine would be transformed,” she said. “Rather than transplant another person’s organ with lifelong immunosuppression, a regenerative treatment could program a patient’s own body to create a needed organ,” she added.

“On a simpler level,” she continued, “regenerating skin and its underlying structures could hasten wound healing and potentially even treat hair loss. This is not a pipe dream, as Waibel has successfully treated severe ulcers using a super gel containing urodele collagen extract. Urodele collagen is type XII collagen, important in the salamander’s capacity to heal and regenerate.”

Waibel disclosed that she is a scientific adviser to RegenX and is a member of the company’s board of directors. Ortiz and Ko reported having no relevant disclosures.