Regeneration without innervation
Ken Muneoka, a professor at the Texas College of Veterinary Medicine and Biomedical Sciences, in a 2019 publication in the journal Nature, proved for the first time that joint regeneration in mammals is possible. Now his group has challenged centuries-old ideas about how mammals can repair damaged body parts.
In humans, only the epidermis, the outer layer of the skin, and some organs, such as the liver, have a natural ability to regenerate. Cold–blooded animals, primarily amphibians and reptiles, are able to restore more complex structures - bones, joints and even whole limbs. Scientists have been studying these species for more than 200 years, trying to understand the mechanisms underlying limb regeneration, in the hope of someday transforming them to cause more intensive regeneration in humans. This led to the general belief that the key to limb regeneration is the presence of nerves.
This may be true for lizards, but it doesn't apply to mammals–according to two recently published studies by Muneoka. The first study, published last year in the Journal of Bone and Mineral Research, showed that mechanical loading (the application of force to the affected area or by itself) is a mandatory requirement for regeneration in mammals. A second study published earlier this year in the journal Development Biology showed that the absence of nerves does not interfere with regeneration. Taken together, these results represent a significant shift in understanding how regeneration can work in humans.
The importance of mechanical loading
Scientists have long believed that two conditions are necessary to trigger regeneration in mammals. The first is growth factors that can stimulate cell division and tissue repair. During natural regeneration, they are produced by the body. For induced regeneration, these growth factors must be injected into the affected area.
The second factor that was always considered necessary was nerves. The belief was based on many studies of human-induced mammalian regeneration in areas (more often on fingers) devoid of nerves. The predictable result is that with the introduction of growth factors, regeneration did not occur, which means that nerves are necessary for regeneration. But the mechanical load aspect was ignored.
In their research, Muneoka and his colleagues decided to take a step back and find out if it's really about nerves, or is the lack of mechanical stress also part of this equation?
Connor Dolan, a former graduate student in Muneoka's lab, came up with a way to test the need for innervation in mammals. He used the hind limb suspension technique, which has been used for decades by NASA and other scientists to test how mammals respond to weightless conditions. A similar process is used during procedures on the paws of large animals so that they do not transfer weight to the affected limbs.
Dolan found that when the limbs of mice were suspended, even if nerves and motor function were preserved, regeneration was completely suppressed. However, the return of the mechanical load restored regeneration. This proved that mechanical loading is an important component of regeneration.
In another experiment, Dolan demonstrated that if a mouse has a finger denervated, but it continues to mechanically affect it, the finger will still recover. Regeneration is a little slower, but completely normal.
Consequences of the study
Thus, previous studies are not completely wrong, they just do not relate directly to people. A number of studies have been conducted on lizards, which proved that when nerves are removed, they do not regenerate. But the processes of limb regeneration in humans are probably closer to mice.
Many scientists do not accept this idea. According to Muneoka, this is due to the fact that their careers depend on nerve research and how they affect regeneration.
Looking to the future
The hypothesis that nerves are not required for regeneration in mammals may seem like an academic question. What is the point of restoring a limb if a person cannot feel or control it without nerves? In this sense, nerves are still an important part of the puzzle. But the point of the work is to think of nerves not as a necessary condition for regeneration, but as part of what needs regeneration.
One of the results of numerous studies on nerves is that scientists have managed to recreate the growth factors that produce nerves and start regeneration in lizards, even if there are no nerves. The authors urge to do the same with the aspect of mechanical loading. Since cells react differently to mechanical stress, somehow this load is biochemically transmitted inside the cell. This means that physical strength can be replaced by some kind of cocktail of molecules that will create the same signals in cells.
Article by C.Dolan et al. Mouse Digit Tip Regeneration Is Mechanical Load Dependent published in the Journal of Bone and Mineral Research; article by C.Dolan et al. Digit specific denervation does not inhibit mouse digit tip regeneration is published in the journal Developmental Biology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on materials from Texas A&M University: New Research Challenges Long-Held Beliefs About Limb Regeneration.