Research into the comparative biology of regeneration suggests that mammals are in principle capable of proficient, full regeneration of complex tissues, but some critical difference in cell signaling and behavior leads instead to the formation of scar tissue in adults. In recent years, scientists have focused on the role of macrophages in coordinating the process of regeneration. In proficient regenerators like salamanders and zebrafish, the presence of macrophages is essential to the regenerative process. Absent macrophages, scar tissue forms in the same way as it does in mammals. Researchers now aim to understand exactly what is different in the behavior of macrophages in mammals and highly regenerative species.
The axolotl, a Mexican salamander that is now all but extinct in the wild, is a favorite model in regenerative medicine research because of its one-of-a-kind status as nature's champion of regeneration. While most salamanders have some regenerative capacity, the axolotl can regenerate almost any body part. Since mammalian embryos and juveniles have the ability to regenerate - for instance, human infants can regenerate heart tissue and children can regenerate fingertips - it's likely that adult mammals retain the genetic code for regeneration, raising the prospect that pharmaceutical therapies could be developed to encourage humans to regenerate tissues and organs lost to disease or injury instead of forming a scar.
Researchers compared immune cells called macrophages in the axolotl to those in the mouse with the goal of identifying the quality in axolotl macrophages that promotes regeneration. The research builds on earlier studies in which it was found that macrophages are critical to regeneration: when they are depleted, the axolotl forms a scar instead of regenerating, just like mammals. The recent research found that although macrophage signaling in the axolotl and in the mouse were similar when the organisms were exposed to pathogens, when it came to exposure to injury it was a different story: the macrophage signaling in the axolotl promoted the growth of new tissue while that in the mouse promoted scarring.
Specifically, the signaling response of a class of proteins called toll-like receptors (TLRs), which allow macrophages to recognize a threat such an infection or a tissue injury and induce a pro-inflammatory response, were unexpectedly divergent in response to injury in the axolotl and the mouse. The finding offers an intriguing window into the mechanisms governing regeneration in the axolotl. The discovery of an alternative signaling pathway that is compatible with regeneration could ultimately lead to regenerative medicine therapies for humans.