Lessons from the Mexican Axolotl: Amphibian Limb Regeneration and Its Impact on Plastic Surgery (2010)

Sir: A major task of plastic surgery is the improvement of extensive scars and problematic wounds. With the exception of fetal scar-free healing, the possibilities for regeneration within humans are limited. A wound that exceeds the basement membrane results in scar formation, which means a rapid and firm but often unsatisfying wound closure. Scar tissue is less resilient and functional, keeping it questionable whether human wound healing is an evolutionarily optimized process. Among amphibians, regeneration in the sense of neoplasm of identical tissue is a common event. The Mexican axolotl (Ambystoma mexicanum) is able to regenerate whole limbs after amputation (Fig. 1) and shows scar-free healing throughout its life. Dedifferentiation of resident cells, initiated and maintained by a limb blastema, leads to a perfect restoration of lost tissue. This process, called epimorphic regeneration, uses mechanisms similar to developmental limb formation.1Fig. 1.: The Mexican axolotl (Ambystoma mexicanum) after experimental amputation. (Image courtesy of Bjoern Menger.)What leads to these regenerative processes? On closer examination, the similarities between fetal and amphibian wound healing seem to concern adaptive immunity. The axolotl lacks adaptive immunity and therefore shows minimal inflammatory response to injury, which also applies to the fetus, whereas adult human skin tends to undergo a rapid restoration by rigid connective tissue accompanied by a strong inflammatory reaction. Recent studies showed the ambivalent role of the immune system in healing processes.2 An interesting consideration would be about which type of wound was liable to evolutionary selection at all. Definitely, it was more the small and medium contaminated wound, because larger injuries surely resulted in death presently. This was a demand for a strong immunologic response and firm closure of wounds. The modern wound (e.g., generated by surgical incision or débridement) often suffers from inflammation, scarring, and fibrosis, as it heals under molecular mechanisms initially selected for the environment of our ancestors. The deprivation of regenerative competence caused by evolutionary demands was presumably accompanied by major variances concerning adaptive immunity. Is this reversible? Consolidated findings suggest that modern wound healing is a conserved, evolutionarily adapted rather than an optimized program. The studies of Odelberg et al.3 showed that dedifferentiation of adult mammalian cells is possible and therefore may be initiated in humans. A similar composition of mediators and signaling pathways raises the hope of using regenerative mechanisms to the good of our patients. Actually, the process of wound healing can be influenced by even minor changes of the composition of growth factors, as the reduced scar formation after experimental use of transforming growth factor-β isoforms has already displayed.4 We can assume that further characterization of the molecular mechanisms underlying amphibian limb regeneration might facilitate the development of therapeutic concepts in wound therapy. The lesson taught by the Mexican axolotl potentially gives direction to compelling advances in plastic and reconstructive surgery. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article. Bjoern Menger, Cand.med., M.D. Kerstin Reimers, Dr.rer.nat., Ph.D. Joern W. Kuhbier, Cand.Med, M.D. Peter M. Vogt, Prof. Dr. med., M.D. Clinic for Plastic, Hand, and Reconstructive Surgery Replantation and Burn Center of Lower Saxony Hannover Medical School Hannover, Germany