Health

Breakthrough Understanding of Limb and Organ Regeneration – Closer to the Development of Regenerative Medicine Therapies

James Godwin with axolotl

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 discovering molecular differences in unraveling the mystery of why salamanders can regenerate while adult mammals cannot do this by signals that promote regeneration in the axolotl, a highly regenerative salamander, while they block it in the adult mouse. Godwin is pictured here with a shell with an axolotl. Photo credit: MDI Biological Laboratory

Discovery in Salamanders by James W. Godwin, Ph.D., advances the science of regenerative medical therapy development.

Many salamanders can easily regenerate a lost limb, but adult mammals, including humans, cannot. Why this is so is a scientific mystery that has fascinated nature watchers for millennia.

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

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

Axolotl

The axolotl, a Mexican salamander that is almost extinct in the wild, is a popular model in regenerative medicine research due to its unique position as a conservationist of regeneration. While most salamanders have some ability to regenerate, the axolotl can regenerate almost any part of the body, including the brain, heart, jaw, limbs, lungs, ovaries, spinal cord, skin, tail, and more. A team of scientists led by James Godwin, Ph.D., of the MDI Biological Laboratory has come one step closer to solving the mystery of why salamanders can regenerate while adult mammals cannot, with the discovery of differences in the molecular signal transmission that enables regeneration in the axolotl, a strongly regenerating salamander, while it blocks it in the adult mouse. Photo credit: MDI Biological Laboratory

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

“Our research shows that humans have untapped potential for regeneration,” said Godwin. “If we can solve the scarring problem, we may be able to unleash our latent regenerative potential. Axolotl do not form scars, which allows regeneration. But as soon as a scar has formed, it’s game over when it comes to regeneration. If we could prevent scarring in humans, we could improve the quality of life for so many people. “

The axolotl as a model for regeneration

The axolotl, a Mexican salamander that is almost extinct in the wild, is a popular model in regenerative medicine research due to its unique position as a conservationist of regeneration. While most salamanders have some ability to regenerate, the axolotl can regenerate almost any part of the body, including the brain, heart, jaw, limbs, lungs, ovaries, spinal cord, skin, tail, and more.

Since mammalian embryos and juveniles can regenerate – for example, human infants can regenerate heart tissue and children regenerate fingertips – it is likely that adult mammals will retain the genetic code for regeneration, increasing the prospect that pharmaceutical therapies could be developed to address the Encourage people to regenerate tissues and organs that have been lost from disease or injury rather than scarring.

Signaling the underlying limb regeneration

This graphic abstract by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, shows the divergence between molecular signals in the immune system of the axolotl, a Mexican salamander that can easily regenerate limbs and other body parts. and the adult mouse that can’t. Photo credit: MDI Biological Laboratory

In his most recent research, Godwin compared immune cells called macrophages in the axolotl to those in the mouse with the aim of identifying the quality of the axolotl macrophages that promote regeneration. The research builds on previous studies in which Godwin found that macrophages are critical to regeneration: when exhausted, the axolotl forms a scar instead of regenerating, just like it does in mammals.

More recent research found that although macrophage signaling in the axolotl and mouse was similar when the organisms were exposed to pathogens such as bacteria, fungi, and viruses, exposure to injury was a different story: macrophage signaling in the axolotl promoted new tissue growth, while that promoted scarring in the mouse.

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

Development dynamics June 2021

Special edition: Salamander models for the elucidation of mechanisms of developmental biology, evolution & regeneration / repair: Part 1

Godwin, who shares a position 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 training on regeneration and the development of new therapies to improve human health.

In particular, the paper reported that the signal response of a class of proteins called toll-like receptors (TLRs) that enable macrophages to detect a threat such as infection or tissue injury and trigger an inflammatory response is “unexpectedly deviant” was. in response to injuries to the axolotl and mouse. The finding offers a fascinating window into the mechanisms of regeneration in the axolotl.

Be able to “pull the levers of regeneration”

The discovery of an alternative signal pathway compatible with regeneration could ultimately lead to regenerative medical therapies for humans. While human limb regrowth may not be realistic in the short term, there is significant potential for therapies that improve clinical outcomes in diseases in which scarring plays an important role in pathology, including heart, kidney, liver and lung diseases.

“We are getting closer and closer to understanding how axolotl macrophages are prepared for regeneration, which brings us closer to pulling the levers on regeneration in humans,” said Godwin. “For example, I envision being able to use a topical hydrogel on the site of a wound that has a modulator added to it that changes the behavior of human macrophages to resemble that of the axolotl.”

Godwin, an immunologist, chose to study the function of the immune system in regeneration because it plays a role in preparing the wound for repair as the equivalent of a first aider 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 that enables axolotl regeneration and scar-free repair.

Reference: “Distinct Toll-like Receptor Signaling in the Salamander response to Tissue Damage” by Ryan J. Debuque, Sergej Nowoshilow, Katya E. Chan, Nadia A. Rosenthal and James W. Godwin, April 1, 2021, Development dynamics.
DOI: 10.1002 / dvdy.340

Godwin’s research is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM103423 and P20GM104318 to the MDI Biological Laboratory. ARMI is supported by grants from the Australian State Government of Victoria. The mouse studies were supported by institutional funds from the Jackson Laboratory.

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