Researchers are set to unravel the mystery of the science behind regeneration

Many salamanders can easily regenerate a lost limb, but adult mammals, including humans, cannot. Why this is the case is a scientific mystery that has fascinated observers of the natural world for thousands of years.

Now, a team of scientists led by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, has come closer to this mystery with the discovery of differences in molecular signaling that promote regeneration in the axolotl , a highly regenerative salamander, while blocking it in the adult mouse, which is a mammal with limited regenerative capacity.

“Scientists at the MDI Biological Laboratory have relied on comparative biology to better understand human health since its founding in 1898,” said Hermann Haller, MD, president of the institution. “The discoveries made possible by James Godwin’s comparative studies on the axolotl and the mouse are proof that the idea of ​​learning from nature is as valid today as it was over 120 years ago. years.”

Instead of regenerating lost or injured body parts, mammals usually form a scar at the site of an injury. Because the scar creates a physical barrier to regeneration, regenerative medicine research at the MDI Biological Lab has focused on understanding why axolotl doesn’t form a scar – or why it doesn’t respond to injury the same way. than the mouse. and other mammals do.

Our research shows that humans have untapped potential for regeneration. If we can fix the problem of scar formation, maybe we can unleash our latent regenerative potential. Axolotls do not heal, which is what allows regeneration. But once a scar has formed, it’s over in terms of regeneration. If we could prevent scars in humans, we could improve the quality of life for so many people. “

James Godwin, PhD, MDI Biological Lab, Bar Harbor, Mount Desert Island Biological Lab

The axolotl as a model of regeneration

The axolotl, an almost extinct Mexican salamander in the wild, is a favorite model in regenerative medicine research because of its unique status as a champion of nature’s regeneration. While most salamanders have some regenerative capacity, axolotl can regenerate almost any part of the body, including the brain, heart, jaws, limbs, lungs, ovaries, spinal cord, skin, tail and more.

Since mammalian embryos and juveniles have the ability to regenerate – for example, human infants can regenerate heart tissue and children can regenerate fingertips – adult mammals are likely to retain the genetic code for regeneration, which suggests that pharmaceutical therapies could be developed to encourage humans to regenerate tissues and organs lost as a result of illness or injury instead of forming a scar.

In his recent research, Godwin compared immune cells called axolotl macrophages to those in mice in an attempt to identify the quality of axolotl macrophages that promote regeneration. The research builds on previous studies in which Godwin found that macrophages are essential for regeneration: When depleted, axolotl forms a scar instead of regenerating, just like mammals.

Recent research has found that although macrophage signaling in axolotl and in mice was similar when organisms were exposed to pathogens such as bacteria, fungi, and viruses, when it came to exposure to injury was a different story: signaling from macrophages in axolotl promoted new tissue growth while that in mice promoted healing.

The research article, titled “Distinct TLR Signaling in the Salamander Response to Tissue Damage” was recently published in the journal Developmental Dynamics. In addition to Godwin, the authors include Nadia Rosenthal, Ph.D., of the Jackson Laboratory; Ryan Dubuque and Katya E. Chan from the Australian Institute of Regenerative Medicine (ARMI); and Sergej Nowoshilow, Ph.D., Institute for Molecular Pathology in Vienna, Austria.

Godwin, who holds a joint appointment with The Jackson Laboratory, was previously associated with ARMI and Rosenthal is the founding director of ARMI. The MDI Biological Laboratory and ARMI have a partnership agreement to promote research and education on regeneration and the development of new therapies to improve human health.

Specifically, the article reported that the signaling response of a class of proteins called toll-type receptors (TLRs), which allow macrophages to recognize a threat such as infection or tissue damage and induce a pro response. -inflammatory, was “unexpectedly divergent” in response to injury in axolotl and mice. The discovery offers an intriguing window into the mechanisms governing regeneration in the axolotl.

To be able to “pull the levers of regeneration”

The discovery of an alternative signaling pathway compatible with regeneration could eventually lead to regenerative medicine therapies for humans. Although regrowth of a human limb may not be realistic in the short term, significant opportunities exist for therapies that improve clinical outcomes in diseases in which scarring plays a major role in pathology, including heart disease. , renal, hepatic and pulmonary.

“We are moving closer to understanding how axolotl macrophages are prepared for regeneration, which will bring us closer to the ability to pull the levers of regeneration in humans,” Godwin said. “For example, I imagine I could use a topical hydrogel at the wound site that is combined with a modulator that changes the behavior of human macrophages to look more like axolotl.”

Godwin, who is an immunologist, chose to examine the function of the immune system in regeneration because of its role in preparing the wound for repairs as the equivalent of a first responder at the site of an injury. . His recent research opens the door to further mapping of critical nodes in TLR signaling pathways that regulate the unique immune environment enabling axolotl regeneration and scar-free repair.


Journal reference:

Debuque, RJ, et al. (2021) Distinct toll receptor signaling in the salamander response to tissue damage. Development dynamics.

About Hector Hedgepeth

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