New research challenges challenge long-held beliefs

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The new research demonstrates that nerves are not necessary for limb regeneration.

The findings suggest a shift in perspective on how regeneration might work in human medicine.

Ken Muneoka has a history of shaking up the regeneration field; for example, in a groundbreaking 2019 article published in Naturethe Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVMBS) professor has proven for the first time the possibility of joint regeneration in mammals.

His team is already challenging other long-held notions about the underlying science of the subject, this time in relation to how mammals might regenerate damaged body parts.

Only certain organs, such as the liver, and certain tissues, such as the epidermis, the upper layer of the skin, can regenerate naturally in humans.

Other species, notably salamanders, have the ability to regenerate complex parts, including bones, joints, and even entire limbs. Therefore, for more than 200 years, researchers have studied these animals in an attempt to understand the processes of limb regeneration in hopes of one day translating these principles to trigger more complete regeneration in humans.

Thanks to this research, it is now widely accepted that the existence of nerves is the most important factor in the regeneration of limbs.

According to two recent studies by Muneoka, while this may be true for salamanders and other species, it is not the case for mammals. The first research, which was published in 2021 in the Journal of Bone and Mineral Research, proved that mammals require a mechanical load, or the ability to exert force on or with an affected location. The second study, recently published in Developmental biologyproved that regeneration is not hindered by lack of nerves.

Together, these findings present a significant shift in thinking about how regeneration might work in human medicine.

“What these two studies show contradicts the two-century-old dogma that it takes nerves to regenerate,” Muneoka said. “What replaces it in mammals is that you need a mechanical load, not nerves.”

Significance of mechanical load

Scientists have long believed that two things must be present in an affected area in order to induce regeneration in mammals. The first concerns growth factors, which are molecules capable of stimulating cell regeneration and rebuilding parts of the body.

In natural regeneration, these growth factors, which vary from species to species and according to the area to be regenerated, are produced by the organism. For human-induced regeneration, these growth factors must be introduced to the area.

The second factor deemed necessary was nerves. This belief was based on many previous studies of human-induced mammalian regeneration on areas, usually fingertips, without nerves, in which entire limbs were also no longer usable.

These studies would have the expected result – when growth factors were introduced, regeneration did not occur – leading to the conclusion that, as in other species, nerves were necessary for regeneration.

But the mechanical load aspect has been ignored.

In their studies, Muneoka and his colleagues decided to take a step back and ask the question, “Is it really the nerves, or is the lack of mechanical load also part of the equation?”

Connor Dolan, a former graduate student in Muneoka’s lab and the first author of the two new studies (who now works at Walter Reed National Military Medical Center), found a way to test the denervation requirement in mammals that was inspired by astronauts.

The technique, called hind limb suspension, has been used by " data-gt-translate-attributes="[{" attribute="">Nasa and other scientists for decades to test how mammals respond to weightless environments. A similar process is used during medical procedures on the legs of large animals to prevent the animals from putting weight on the affected limbs.

“Dolan found that when the limbs were suspended, even though they still had a lot of nerve and could move, they couldn’t actually put pressure on their limbs so that the fingertips didn’t regenerate,” said Muneoka. “It completely inhibited regeneration.”

As soon as the mechanical load returns, however, the regeneration is saved.

“Absolutely nothing happens during suspension,” Muneoka said. “But once the charge comes back, there will be a few weeks of delay, but then they will start to regenerate.”

This first step proved that while nerves might be necessary, mechanical loading was an essential part of regeneration.

Taking the research a step further, Dolan’s second publication showed that nerves were not necessary by demonstrating that if a mouse has no nerves in one of its fingers but has nerves in the others – from so that she is still exerting force on the denervated finger – that finger will still regenerate.

“He found that they regenerate a bit slower, but they regenerate perfectly normally,” Muneoka said.

Research ramifications

Muneoka is quick to point out that their studies aren’t saying previous research is wrong, just that they don’t directly apply to humans.

“There have been a number of studies on salamanders that prove that when you take the nerves out, they don’t regenerate,” Muneoka said. “Researchers were also able to introduce growth factors into cells that they know are produced by nerves and rescue regeneration.

“So salamanders probably need nerves to regenerate,” he said. “But if we want to regenerate limbs in humans, it will be much more like what happens in mice.”

Since he first became interested in regeneration over 20 years ago, a number of Muneoka’s ideas have challenged generally accepted theories of regeneration. He said it took almost three years for these two articles to be published because they initially tried to submit them together.

“Many scientists don’t embrace this idea,” he said. “A lot of people’s careers really depend on their studies of nerves and how they affect regeneration. For a study to come out and say that for humans, you’re unlikely to need nerves, any the biomedical application of what people do in salamanders and fish kind of goes out the window.

Look on the road

Nerves not being necessary for regeneration in mammals might seem like an academic point. After all, what would be the point of regenerating a limb if the person couldn’t feel it or control it because it had no nerves? In that sense, nerves are always going to be an important part of the puzzle.

From Muneoka’s perspective, the change is that instead of looking at nerfs as a requirement for regeneration, nerfs are part of what needs to be regenerated.

Larry Suva, head of the Department of Veterinary Physiology and Pharmacology (VTPP) at CVMBS, explains that the problem is that no one even thought about the bulking aspect before.

“Think of a blast wound where a soldier ends up with a stump,” Suva said. “No one, until the publication of this article, even thought of a requirement for mechanical influences. You’ve seen people say that a denervated animal doesn’t regenerate and they think it’s because the nerve has been cut, but nobody was studying the mechanical load aspect.

As Suva says, science is full of people looking for where the light is best.

“I work on bones, so when I see a problem, I look at the bone problem,” he said. “People who work on the nerves, all they look at are the nerves. So it’s very rare that someone like Dr. Muneoka takes a step back and takes a more holistic view.

“That’s what he brought to this idea, to this 200-year-old data,” Suva said. “Now we need to look at regeneration from a different angle, because we now know that mechanical influences are extremely important.”

One result of the nerve-focused research is that the scientists were able to recreate the growth factors produced by the nerves, allowing the researchers to begin salamander regeneration even when the nerves were not present. Suva said that with these new findings, scientists will now know that they must do the same with the aspect of mechanical loading if they are to begin regeneration in mammals.

“Scientists have already managed to trick the body into thinking that the nerves are still there,” he said. “But now they know they’ll also have to make them believe there’s a mechanical load, something that’s never been done before.”

Because cells respond differently under mechanical load, one way or another, that load is biochemically translated inside the cell.

“There are a small number of labs studying the biochemical basis of what mechanical loading does to a cell,” Muneoka said. “If we could understand this biochemical signal, then perhaps the physical force of mechanical load could be replaced by some sort of cocktail of molecules that will create the same signals in cells.”

The end of the road to full human regeneration may still be a long way off in the future, but Suva says this kind of fundamental shift in thinking is a major marker on that road.

“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 with growth factors,” he said. he declares. “It changes the way future scientists and engineers are going to solve this problem.

“There are still a number of complex issues that need to be resolved before regeneration of whole human limbs is possible, but Dr. Muneoka’s findings are an important next step in ensuring we are addressing the right issues.”

References: “Mouse Digit Tip Regeneration Is Mechanical Load Dependent” by Connor P Dolan, Felisha Imholt, Tae-Jung Yang, Rihana Bokhari, Joshua Gregory, Mingquan Yan, Osama Qureshi, Katherine Zimmel, Kirby M Sherman, Alyssa Falck, Ling Yu, Eric Leininger, Regina Brunauer, Larry J Suva, Dana Gaddy, Lindsay A Dawson and Ken Muneoka, November 16, 2021, Journal of Bone and Mineral Research.
DOI: 10.1002/jbmr.4470

“Specific digit denervation does not inhibit mouse digit tip regeneration” by Connor P. Dolan, Felisha Imholt, Mingquan Yan, Tae-Jung Yang, Joshua Gregory, Osama Qureshi, Katherine Zimmel, Kirby M. Sherman, Hannah M. Smith, Alyssa Falck, Eric Leininger, Ling Yu, Regina Brunauer, Larry J. Suva, Dana Gaddy, Lindsay A. Dawson, and Ken Muneoka, March 31, 2022, Developmental biology.
DOI: 10.1016/j.ydbio.2022.03.007

The study was funded by the Defense Advanced Research Projects Agency.

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