Macrophages Essential to Limb Regeneration in the Axolotl Emerge from the Liver

Regeneration from injury is an intricate dance between stem cells, somatic cells, senescent cells, and immune cells. In particular, research into the biochemistry of species such the axolotl that can regenerate limbs and organs has identified the innate immune cells known as macrophages as essential to the process. Specific differences in macrophage behavior between more regenerative species such as the axolotl and less regenerative species such as our own are still under exploration. Here, researchers uncover a greater level of complexity in axolotl regeneration, in that only some macrophages are important to scar-free regeneration, and these cells originate in the liver rather than the bone marrow.

In 2013 it was discovered that a type of white blood cell called a macrophage is essential to limb regeneration in the axolotl. Without macrophages, which are part of the immune system, regeneration did not take place. Instead of regenerating a limb, the axolotl formed a scar at the site of the injury, which acted as a barrier to regeneration, just as it would in a mammal such as a mouse or human. Now, in a new study, researchers have identified the origin of pro-regenerative macrophages in the axolotl as the liver. By providing science with a place to look for pro-regenerative macrophages in humans - the liver, rather than the bone marrow, which is the source of most human macrophages - the finding paves the way for regenerative medicine therapies in humans.

Although the prospect of regrowing a human limb may be unrealistic in the short term due to its complexity, regenerative medicine therapies could potentially be employed in the shorter term in the treatment of the many diseases in which scarring plays a pathological role, including heart, lung and kidney disease. "If axolotls can regenerate by having a single cell type as their guardian, then maybe we can achieve scar-free healing in humans by populating our bodies with an equivalent guardian cell type, which would open up the opportunity for regeneration."

Although it remains to be seen if achieving scar-free healing in mammals will allow regeneration to proceed, researchers believe that may be the case. Because mammals already possess the machinery for regeneration - young mice can regenerate, as can human newborns - mammalian regeneration may simply be a matter of removing the barrier posed by scarring. "In axolotls, macrophages act as a brake on fibrosis, or scarring. Humans may possess macrophages that are doing their hardest to repair the damage, but are being held back. If we can engineer human macrophages to promote scar-free healing, we might be able to achieve a huge improvement in repair with just a little tweak. We have the luxury in the salamander of being able to work out which macrophage functions are essential to scar suppression and regeneration, gene by gene if we have to. If we can find out what that is, then maybe we can get that interaction happening in mammals."



I would have more hopes for translating to humans the findings on the spiny mouse regeneration. Axolotls have split away from us some 370 million years ago, while our split from rodents was "only" 85 million years ago. From evolutionary and genetic POV mice are closer to us than dogs.

Posted by: Cuberat at November 26th, 2021 7:01 AM

So are these macrophages responsible for the high regenerative capacity of the liver in humans and other mammals?

Posted by: Antonio at November 26th, 2021 3:38 PM

Recently I have learnt that technically human liver doesn't regenerate much. it is rather a type of hyperplasia where the remaining organ grows in size and takes over the missing tissues. For a relatively "simple" and uniform organ that's good enough.

Posted by: Cuberat at November 26th, 2021 4:37 PM

I'm with you on hoping that the spiny mouse findings are amenable to translation to humans. Our immune compartment is the most plastic system within our bodies. The cells have no continuous physical connections, no network or critical contacts, and are generally interchangeable as demonstrated by our ability to conduct bone marrow transplants and CAR-T therapy.

It'd be nice to think someone was hard at work engineering our macrophages to direct repair in a manner similar to the spiny mouse, but I doubt it's happening yet.

Maybe Reason is working on it!

Posted by: Robert Cargill at November 26th, 2021 5:07 PM

@Robert Cargill
That would be to expecting to much from Reason and his partners. While they are real (super) heroes. They are working on so many things already.

On the other hand, they already have the experience and skills to manipulate macrophages and a roadmap to make them immuno compatible and potentially cheap enough , of mass produced. A plausible bet would be an intervention which reduces scaring and slightly improves the recovery. Even a small effect , of robust , can make a big difference in post traumatic and post operative recovery. That would attract funding and interest so the second and next generations might do more serious regeneration.

Posted by: Cuberat at November 26th, 2021 7:54 PM

Scar-free healing can already be acheived in humans in some circumstances eg surgery performed on newborn infants for hair lip can obtain excellent results if done very soon after birth. Wait only a few months and the outcomes become less impressive. Wait until adulthood and the result is never as good.
A similar effect is seen in female adult pelvic tissue after delivery when quite major trauma - say a large episiotomy to aid delivery- can be almost totally without trace six weeks later.
There must be a variation in the immune/scar response to explain this.

Posted by: JLH at November 26th, 2021 9:54 PM

In my first large readings of aging science about 20 years ago, I remember that someone was observing tissues in the regeneration of the liver and of salamander legs, and concluded that oval cells seemed to be recruted to avoid scar, for regeneration. I don't know how "has been" this is, I just mention it because sometime old careful obsversation science crosses well with more techy recent science.

I just googled liver ovel cells axolots and finds that there is a comparison of liver repair/hyperplasia across species incl. axolots : For those interested my guess it that this type of comparison can help judge if the regrowth of the liver with oval cells is similar to the regrowth of legs or if it is two very different stories, and post here the analysis. Perhaps I should chime in here without doing the work myself..

Posted by: Edouard Debonneuil at January 9th, 2023 3:12 PM
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