Vitruvian Man Human Anatomy Skeleton

Nuevas investigaciones desafían creencias de larga data


La nueva investigación demuestra que los nervios no son necesarios para la regeneración de las extremidades.

Los resultados sugieren un cambio de perspectiva sobre cómo podría funcionar la regeneración en la medicina humana.

Ken Muneoka tiene un historial de sacudir el campo de la regeneración; por ejemplo, en un artículo innovador de 2019 publicado en Naturalezael profesor de la Facultad de Medicina Veterinaria y Ciencias Biomédicas de la Universidad Texas A&M (CVMBS) demostró por primera vez la posibilidad de regeneración conjunta en mamíferos.

Su equipo ya está cuestionando otras nociones arraigadas sobre la ciencia subyacente del tema, esta vez en relación con la forma en que los mamíferos podrían regenerar partes dañadas del cuerpo.

Solo algunos órganos, como el hígado, y ciertos tejidos, como la epidermis, la capa superior de la piel, pueden regenerarse naturalmente en los humanos.

Otras especies, sobre todo las salamandras, tienen la capacidad de regenerar partes complejas como huesos, articulaciones e incluso extremidades enteras. En consecuencia, durante más de 200 años, los investigadores han estudiado a estos animales para intentar comprender los procesos detrás de la regeneración de las extremidades con la esperanza de traducir algún día esos principios para desencadenar una regeneración más completa en los humanos.

Debido a esta investigación, ahora se acepta ampliamente que la existencia de nervios es el factor más importante en la regeneración de las extremidades.

Según dos de los estudios recientes de Muneoka, aunque puede ser cierto para las salamandras y otras especies, no lo es para los mamíferos. La primera investigación, que se publicó en 2021 en el Revista de investigación ósea y mineral, demostró que los mamíferos necesitan carga mecánica, o la capacidad de ejercer fuerza sobre o con un lugar afectado. El segundo estudio, que se publicó recientemente en Biología del desarrollodemostró que la regeneración no se ve obstaculizada por la falta de nervios.

Juntos, estos hallazgos presentan un cambio considerable en el pensamiento de cómo la regeneración podría funcionar en la medicina humana.

“Lo que muestran estos dos estudios contrarresta el dogma de hace dos siglos de que se necesitan nervios para regenerarse”, dijo Muneoka. “Lo que lo reemplaza en los mamíferos es que necesitas carga mecánica, no nervios”.

Importancia de la carga mecánica

Los científicos han creído durante mucho tiempo que dos cosas deben estar presentes en un área afectada para inducir la regeneración en los mamíferos. El primero son los factores de crecimiento, que son moléculas que pueden estimular a las células para que vuelvan a crecer y reconstruir partes del cuerpo.

En la regeneración natural, estos factores de crecimiento, que varían de una especie a otra y según el área que se está regenerando, son producidos por el cuerpo. Para la regeneración inducida por el hombre, estos factores de crecimiento deben introducirse en el área.

El segundo factor que se creía necesario eran los nervios. Esta creencia fue predicada por muchos estudios previos de regeneración de mamíferos inducidos por humanos en áreas, generalmente puntas de los dedos, sin nervios, en las que las extremidades completas ya no eran utilizables.

Esos estudios tendrían el resultado previsto: cuando se introdujeron los factores de crecimiento, la regeneración no tuvo lugar, lo que llevó a la conclusión de que, como en otras especies, los nervios eran un requisito para la regeneración.

Pero se ignoró el aspecto de la carga mecánica.

En sus estudios, Muneoka y sus colegas decidieron dar un paso atrás y hacer la pregunta: “¿Son realmente los nervios o la falta de carga mecánica también es parte de la ecuación?”

Connor Dolan, un exestudiante graduado en el laboratorio de Muneoka y el primer autor de ambos nuevos estudios (que ahora trabaja en el Centro Médico Militar Nacional Walter Reed), ideó una forma de probar el requisito de denervación en mamíferos que se inspiró en los astronautas.

La técnica, llamada suspensión de las patas traseras, ha sido utilizada por[{” attribute=””>NASA and other scientists for decades to test how mammals react to zero gravity 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 lots of nerves and could move around, they couldn’t actually put pressure on their limbs so the digit tips wouldn’t regenerate,” Muneoka said. “It just completely inhibited regeneration.”

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

“Absolutely nothing happens during the suspension,” Muneoka said. “But once the load returns, there will be a couple of weeks of delay, but then they’ll begin to regenerate.”

That first step proved that even though nerves might be required, mechanical loading was a critical component of regeneration.

Taking the research a step further, Dolan’s second publication showed that nerves weren’t required by demonstrating that if a mouse has no nerves in one of its digits but does in the others — so that it’s still exerting force on the denervated digit—that digit will still regenerate.

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

Ramifications Of The Research

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

“There have been a number of studies in salamanders that prove that when you remove the nerves, they do not regenerate,” Muneoka said. “Researchers have also been able to put growth factors they know are being produced by nerves into the cells and rescue regeneration.

“So, salamanders probably do need nerves to regenerate,” he said. “But if we’re going to regenerate limbs in humans, it’s going to be a lot more like what happens in mice.”

Since first beginning to look at regeneration more than 20 years ago, a number of Muneoka’s ideas have pushed back against the generally accepted theories about regeneration. He said that getting these two papers published took almost three years because they originally tried to submit them together.

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

Looking Down The Road

Nerves not being required for regeneration in mammals may 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 still going to be an important part of the puzzle.

From Muneoka’s perspective, the shift is that instead of thinking of nerves as a requirement for regeneration, nerves are a part of what needs to be regenerated.

Larry Suva, head of the CVMBS’ Department of Veterinary Physiology & Pharmacology (VTPP), says the issue is that nobody was even thinking about the load aspect previously.

“Think of a blast injury where a soldier is left with a stump,” Suva said. “No one, until this paper came out, was even thinking about a requirement from mechanical influences. You had people see that a denervated animal doesn’t regenerate and they’re thinking it’s because the nerve was cut, but nobody was studying the mechanical load aspect.”

As Suva puts it, science is full of people looking 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 nerves, all they look at are nerves. So it’s very rare that someone like Dr. Muneoka will take a step back and take a more holistic view.

“That’s what he brought to this idea, to this 200-year-old data,” Suva said. “We now have to look at regeneration through a different lens because now we know the mechanical influences are extremely important.”

One of the results of research focusing on nerves is that scientists have been able to recreate the growth factors that nerves produce, which has allowed researchers to start regeneration in salamanders, even if the nerves aren’t present. Suva said that with these new findings, scientists will now know they have to do the same with the mechanical load aspect if they want to start regeneration in mammals.

“Scientists already have been able to trick the body into thinking nerves are still present,” he said. “But now they know they’ll also have to trick it into thinking there’s a mechanical load, something that has not been done before.”

Because cells react differently under mechanical load, somehow, that load is being translated biochemically inside the cell.

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

The end of the road toward full human regeneration may still be a long way in the future, but Suva says that 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 along with the growth factors,” he said. “That changes how future scientists and engineers are going to solve this problem.

“There are still a number of complex problems to be solved before regenerating entire human limbs is possible, but Dr. Muneoka’s findings are an important next step to make sure we’re solving the right problems.”

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, 16 November 2021, Journal of Bone and Mineral Research.
DOI: 10.1002/jbmr.4470

“Digit specific 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, 31 March 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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