MDI Biological Laboratory

Who Is Coming to the Regeneration Party?

  • November 10, 2021

New Research by James Godwin, Ph.D., in the Axolotl Offers Insight Into the Role of the Various Players at the Site of an Injury 

MDI Biological Laboratory scientist, James Godwin, Ph.D., who studies heart and limb regeneration in the axolotl, a highly regenerative Mexican salamander, likes to compare the process of regeneration that takes place at the site of an injury to a party.

Over the course of his career, he has identified who comes to the regeneration party (a type of immune system cell called a macrophage); where the macrophages come from (the liver); and how they get there. The presence of these macrophages is what gives the axolotl its amazing ability to regenerate almost any body part including brain, heart, jaws, limbs, lungs, ovaries, skin, spinal cord, tail and more.

By contrast, the regeneration party at the site of wound in an adult mammal such as a mouse or human is a bust. Though macrophages show up, they are the wrong sort. Instead of launching the regenerative process as they do in the axolotl, they set off a “horrible,” to use Godwin’s word, pathological process that leads to inflammation and scarring, or fibrosis, which creates a physical barrier to regeneration.

Godwin’s description of regeneration took place in a conversation about his recent paper in Frontiers in Cell and Developmental Biology, which identified the source of pro-regenerative macrophages in the axolotl as the liver. By giving it a place to look for them, the identification of the source of pro-regenerative macrophages as the liver brings science a step closer to developing drugs to promote regeneration in humans.

Having identified the type of guest that comes to the party and, now, where those guests come from, Godwin’s next mission is to profile the guests’ identities – to use his words, to identify the “flavors” of macrophages that promote regeneration – and to find out what they are saying to other guests, the fibroblasts, a type of connective tissue cell responsible for orchestrating the process of regeneration.

And that’s where the stuff of science fiction starts to look like a real possibility.

Once Godwin has profiled pro-regenerative macrophages, it may be possible to a.) tease pro-regenerative macrophages out of the mammalian system (he believes that they likely are there, but that they are elusive); or b.) engineer mammalian macrophages to be more like an axolotl’s. Though either approach sounds like a tall order, clues hint that human regeneration may not be as difficult as it sounds.

Science doesn’t yet know if the achievement of scar-free healing would be enough on its own to promote regeneration in humans – other processes may also be involved – but Godwin’s thinks that that just might be the case.

“If we can engineer human macrophages to promote scar-free healing that supports regeneration, we might be able to achieve a huge improvement in repair with just a little tweak. Wouldn’t it be awesome if we didn’t have to do anything other than that?”

Supporting this idea is the fact that young mice can regenerate, as can human newborns, an ability that is lost as they get older. The evidence that the machinery for regeneration already exists in mammals raises the tantalizing prospect that medicine could one day tap into it. “As Godwin puts it: “It could be that we already know how to regenerate, but that that pesky scar tissue gets in the way.”

Another intriguing hint that regeneration may be possible in humans has to do with the source of pro-regenerative macrophages. In his recent paper, Godwin identified the source in the axolotl as the liver, which is also the source in the newborn mouse. It is only when the bone marrow takes over as the source of macrophages as the mouse matures that it loses its capacity for scar-free healing.

Though the axolotl has become a popular regenerative biology model because of its astounding regenerative capabilities, it lacks many of the tools that have been developed for working with more established animal models. One of Godwin’s achievements is the development of a toolkit for profiling and sorting subsets of the axolotl immune cell population, which was also described in the recent paper.

Using this toolkit, Godwin’s next task is to assess the various functions of pro-regenerative macrophages in the regenerative process, starting with their role in blocking fibrosis.

“We have to find out what signals the macrophages are giving to the fibroblasts – they must be telling them something,” Godwin said. “If we can find out what that interaction is, then maybe we can get that interaction happening in mammals.”

In other words, after profiling the guests at the regeneration party, his next job will be to capture what they are saying.