Ken Muneoka, a professor at the Texas A&M University College of Veterinary Medicine & Biomedical Sciences, proved for the first time that joint regeneration in mammals was possible in a ground-breaking publication.
His team is challenging old beliefs about the fundamental science of the field, this time related to how mammals can repair damaged parts of the body.
The ability to regenerate in humans is limited to a few tissues, such as the skin and the body's internal organs.
salamanders have the ability to regenerate bones, joints, and even entire limbs. Scientists have been studying these species for more than 200 years in an attempt to understand the mechanisms behind limb regeneration in hopes of one day being able to induce more extensive regeneration in humans.
A common belief is that nerves are the most important factor in limb regeneration.
It isn't the case in mammals, according to two Muneoka studies. The ability to apply force to or with an affected area is a requirement for mammals. The second published earlier this year shows that the absence of nerves doesn't affect regeneration.
There is a big shift in the thinking of how regeneration could be used in human medicine.
Two studies show that nerves don't need to be regenerated. Nerves are replaced in mammals by mechanical loading.
The importance of mechanical load.
In order to induce regeneration in mammals, there must be two things present. Growth factors aremolecules that can help cells to regrowth and reconstruct.
Growth factors that vary from species to species are produced by the body. Growth factors need to be introduced to the area.
There were two factors believed to be necessary. The belief was based on studies done on areas where the limbs were no longer usable.
The studies would lead to the conclusion that nerves were required for regeneration when growth factors were not used.
The mechanical load was not taken into account.
Muneoka and colleagues decided to ask the question, "is it really the nerves, or is lack of mechanical load part of the equation?"
A former graduate student in Muneoka's lab came up with a way to test the denervation requirement in mammals that was inspired by astronauts.
NASA has used the technique for decades to test how mammals respond to zero gravity environments. During medical procedures on legs of large animals, a similar process is used to prevent the animals from putting too much weight on the limbs.
"Dolan discovered that when the limbs were suspended, they couldn't put pressure on their limbs so the digit tips wouldn't regenerate," Muneoka said. It stopped regeneration.
Regeneration is saved when the mechanical load comes back.
Muneoka said there was absolutely nothing happening during the suspension. Once the load returns, there will be a couple weeks of delay, but then they will start regenerating.
Even though nerves might be required, the mechanical loading was crucial to regeneration.
The second publication shows that if a mouse has no nerves in one of its digits but does in the others, it will still regenerate.
Muneoka said that he found that they regenerated perfectly.
There are repercussions of the research.
Muneoka points out that their studies aren't saying that previous research is wrong, just that it doesn't apply to humans.
A number of studies show that salamanders don't regenerate when the nerves are removed. Researchers have been able to put growth factors into the cells that are being produced by nerves.
salamanders probably need nerves to grow It's going to be a lot more similar to what happens in mice if we're going to regenerate limbs in humans.
A number of Muneoka's ideas have pushed back against the accepted theories about regeneration. It took almost three years for these two papers to be published.
He said that many scientists don't like the idea. A lot of people's careers are dependent on how they study nerves. The whole application of what people are doing in salamanders and fish goes out the window if a study says that for humans.
Down the road is where I am looking.
Nerves aren't required for regeneration in mammals. What would be the point of regenerating a limb if the person couldn't feel it or control it because they weren't used to it? Nerves will be an important part of the puzzle.
Instead of thinking of nerves as a requirement for regeneration, nerves are a part of what needs to be regenerated.
The issue is that nobody thought about the load aspect before.
A soldier who has been injured in a blast is left with a stump. Until this paper came out, no one had considered a requirement from mechanical influences. People saw that a denervated animal doesn't regenerate and they thought it was because the nerve was cut, but nobody was studying the mechanical load aspect.
Science is filled with people looking at where the best light is.
He works on bones, so when he sees a problem, he looks at it. People who work on nerves are the most nervous of all people. It is very rare for someone like Dr. Muneoka to take a moreholistic view.
He brought this idea to the data of 200 years ago. The mechanical influences are important and now we have to look at regeneration through a different lens.
Scientists have been able to recreate the growth factors that nerves produce, which has allowed them to start regenerating salamanders even if the nerves aren't present. If scientists want to start regeneration in mammals, they have to do the same thing with mechanical load.
He said that scientists have been able to trick the body into thinking it's not dead. They will have to trick it into thinking there is a mechanical load, something that has never been done before.
The load is being translated into the cell by the cells' reactions under mechanical load.
The biochemical basis for what mechanical load does to a cell is being looked at by a few labs. The physical force of mechanical load can be replaced by a cocktail of molecule that will create the same signals in the cells.
The end of the road towards full human regeneration is still a long way off, but this kind of fundamental shift in thinking is a major marker on that road.
He said that "regeneration of a human limb may still be science fiction, but we know some facts about it, and now we know you have to have that mechanical load along with the growth factors" Future scientists and engineers will solve this problem differently because of that.
There are still a number of complex problems to be solved before regenerating entire human limbs, but Dr. Muneoka's findings are an important next step.
More information: Connor P. Dolan et al, Digit specific denervation does not inhibit mouse digit tip regeneration, Developmental Biology (2022). DOI: 10.1016/j.ydbio.2022.03.007
All Rights Reserved © 2024
