How frequently have you noticed superheroes and supervillains in an english comic or a hollywood movie? Quite frequently, I bet. The one thing most common is their ability to dodge bullets or to simply pull it out of their body and continue their combat. While, a superhero doing this looks quite simple (only because of the CGI and VFX), a typical human won’t survive. The prime biological reason that can be used to explain this is inability to regenerate. Mammals are biologically incapable of regenerating their tissues, except for the compensatory regeneration reported in liver. The bullet or any other injury, if harms our vital organs, makes us prone to serious complications, if not sudden death. Some other organisms, on the other hand show commendable capabilities to regenerate. Axolotl, for example (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 the nature’s champion of regeneration. While most salamanders have some regenerative capacity, the axolotl can regenerate almost any body part, including brain, heart, jaws, limbs, lungs, ovaries, spinal cord, skin, tail, and more. This difference between the regeneration capabilities of mammals and a salamander has remained an area of interest for scientists and for the entire scientific community.
Axolotl vs Mammalian Rat
Salamanders have been hailed as champions of regeneration exhibiting remarkable capabilities. They have been reported to regrow organs as complicated as entire limbs, heart, or even the entire body itself. For long, the reason behind this could not be speculated. But with advancements in biological sciences and specifically in molecular signalling patterns, some new evidences have been found supporting the research. One such study of the axolotl reveals that the ability of regeneration relies in their immune system.
A team of scientists led by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, has come a step closer to unraveling the mystery of why salamanders can regenerate while adult mammals cannot. They revealed that immune cells called macrophages are critical in the early stages of regeneration of lost limbs. Knocking out these cells prevented regeneration and led to tissue scarring. The discovery enabled a comparative study for the differences of regeneration in axolotl and mouse.
Differences in regeneration:
It has been almost exclusively proved that the axolotl is the superior candidate in the regeneration race against the mouse. However, the mouse or mammals for instance are not completely lacking this ability. Mammalian embryos and juveniles have been found to pursue the ability to regenerate — for example, human infants can regenerate heart tissue and children can regenerate fingertips. This evidence is enough for the scientists to claim that adult mammals do retain the genetic code for regeneration, thus, raising the prospect that pharmaceutical therapies could be developed in order to encourage humans to regenerate tissues and organs lost due to diseases or injuries.
Regeneration vs Scarring:
The prime reason behind this success of axolotl and loss of mammals owes to the procedure of scar formation in mammals, which is absent in axolotl. Regeneration refers to the complete replacement of damaged tissues with new tissue irrespective of scar formation, while on the other hand repair or wound healing is a mechanism of restoration or re-establishing the tissue continuity, which very often results into scarring. Instead of regenerating lost or injured body parts, mammals typically form a scar at the site of an injury. The scar is in order to maintain tissue continuity which thus, creates a physical barrier to regeneration. This led researchers at the MDI Biological Laboratory to focus on understanding why the axolotl doesn’t form a scar! Why their response to injury is different from that of a mouse or any other mammal.
If somehow we succeed in solving the problem of scar formation, we possibly can unlock our latent regenerative potential. Axolotls don’t scar, which is what allows regeneration to take place. But once scar has come to its role, regeneration is knocked out. If we could unlock the doors for this potential regeneration power in humans, we can surely enhance the quality of life for so many people.
Role of Macrophages:
A very strange aspect of immune cells in regeneration came to light, apart from being phagocytic in nature and building the first line of defence. A research team lead by James Godwin found that- macrophages are critical to regeneration. It was supported by the evidence where the decline in number of macrophages also led to decrease in regeneration capacity of the axolotl. As a result, the axolotl started behaving similar to mammals in response to injuries without showing significant signs of regeneration. Although, macrophage signaling in the axolotl and in the mouse were similar when the organisms were exposed to pathogens such as bacteria, fungi and viruses. Their response on exposure to injury was a different story- the macrophage signaling in the axolotl promoted the growth of new tissue while that in the mouse promoted scarring.
Recently a paper was published in a journal named “Developmental Dynamics” which points out the role of Toll-like rececptor signalling in assisting the macrophages response to tissue or organ injury. These receptors allowed macrophages to recognize a threat such as infection or a tissue injury and backed them with a pro-inflammatory response, which provides great diversity in response to injury in the axolotl and the mouse.
Regeneration in the Animal Kingdom:
The absence of an appendage, such as a limb or a tail, will lead to inefficient locomotion, thus resulting in a decreased survival rate. Myocardial infarction disrupts the performance of the blood‐pumping organ, leading to a life‐threatening condition. However, survival of the organism with respect to this initial trauma will further be lead by complete organ regeneration. This feature intuitively provides an advantage to regain fitness after injury. Ironically, majority of lower vertebrates are reported to possess an innate ability to restore their damaged appendages and the heart, mammals evidently lack this capability. This polarity in the animal kingdom towards regeneration could be due to various constraints of anatomical, physiological and molecular nature, such as the high complexity of the mammalian organs, a cytokine profile of inflammatory cells and inaccessible morphogenetic information, which arose as adaptive traits or as side‐effects of other evolutionary changes. Among many concepts, the classic hypothesis proposes that the regenerative capability declines whenever the lost part of organ becomes absolutely indispensable for survival.
The transition of animals from aquatic to terrestrial habitat coincides with the reduction of limb‐regenerative capability. Fish and aquatic urodeles possess the ability to completely and efficiently reproduce amputated appendages. Postmetamorphic terrestrial frogs and toads completely lack this capability, while aquatic Xenopus froglets are capable of heteromorphic regeneration. Amniotic vertebrates, i.e. reptiles, birds and mammals, which adapted to life and reproduction on the land, display no limb regeneration. A certain capacity of appendage restoration can be regained, as exemplified by digit tip regeneration in mice and humans under certain circumstances.
Take your call:
With the ongoing studies in developmental biology and their correlation with immunology, scientists have been able to identify new principles and procedures of cellular behaviour responsible for regeneration. Very soon the sky stepping advancement in science and technology will create a breakthrough in unveiling the process of less progressive regeneration in humans. We are very close to understanding how axolotl macrophages are primed for regeneration, which significantly will open doors for new alternatives of organogenesis and organ transplant.
Reference: Developmental dynamics journal ; MDI Biological laboratory